As a law student, O'Connell was aware of his own talents, but the higher ranks of the Bar were closed to him. He read the Jockey Club as a picture of the governing class in England, and was persuaded by it that, "vice reigns triumphant in the English court at this day. The spirit of liberty shrinks to protect property from the attacks of French innovators. The corrupt higher orders tremble for their vicious enjoyments." O'Connell's studies at the time had concentrated upon the legal and political history of Ireland, and the debates of the Historical Society concerned the records of governments, and from this he was to conclude, according to one of his biographers, "in Ireland the whole policy of the Government was to repress the people and to maintain the ascendancy of a privileged and corrupt minority."

On 3 January 1797, he wrote to his uncle saying that he was the last of his colleagues to join a volunteer corps and 'being young, active, healthy and single' he could offer no plausible excuse. Later that month, for the sake of expediency, he joined the Lawyer's Artillery Corps.

On 19 May 1798, O'Connell was called to the Irish Bar and became a barrister. Four days later the United Irishmen staged their rebellion which was put down by the British with great bloodshed. O'Connell did not support the rebellion; he believed that the Irish would have to assert themselves politically rather than by force. He went on the Munster circuit, and for over a decade he went into a fairly quiet period of private law practice in the south of Ireland. He also condemned Robert Emmet's rebellion of 1803. Of Emmet, a Protestant, he wrote: 'A man who could coolly prepare so much bloodshed, so many murders — and such horrors of every kind has ceased to be an object of compassion.'

O'Connell returned to politics in the 1810s. In 1811, he established the Catholic Board, which campaigned for only Catholic Emancipation, that is, the opportunity for Irish Catholics to become Members of Parliament. In 1823, he set up the Catholic Association which embraced other aims to better Irish Catholics, such as: electoral reform, reform of the Church of Ireland, tenants' rights, and economic development. The Association was funded by membership dues of one penny per month, a minimal amount designed to attract Catholic peasants. The subscription was highly successful, and the Association raised a large sum of money in its first year. The money was used to campaign for Catholic Emancipation, specifically funding pro-emancipation Members of Parliament (MPs) standing for the British House of Commons.

In 1815 a serious event in his life occurred. The Dublin Corporation had always been reactionary and bigoted against Catholics, and served the established Protestant Ascendancy. O'Connell in an 1815 speech referred to "The Corpo", as it was commonly referred to, as a "beggarly corporation". Its members and leaders were outraged and because O'Connell would not apologize, one of their number, the noted duellist John D'Esterre, challenged him. The duel had filled Dublin Castle (from where the British Government administered Ireland) with tense excitement at the prospect that O'Connell would be killed. They regarded O'Connell as "worse than a public nuisance," and would have welcomed any prospect of seeing him removed at this time. O'Connell met D'Esterre and mortally wounded him (he was shot in the hip, the bullet then lodging in his stomach), in a duel at Oughterard, County Kildare. His conscience was bitterly sore by the fact that, not only had he killed a man, but he had left his family almost destitute. O'Connell offered to "share his income" with D'Esterre's widow, but she declined; however, she consented to accept an allowance for her daughter, which O'Connell regularly paid for more than thirty years until his death. The memory of the duel haunted him for the remainder of his life.

As part of his campaign for Catholic Emancipation, O'Connell created the Catholic Association in 1823; this organization acted as a pressure group against the British government so as to achieve Emancipation. The Catholic Rent, which was established in 1824 by O'Connell and the Catholic Church raised funds from which O'Connell was able to help finance the Catholic Association in its push for emancipation. O'Connell stood in a by-election to the British House of Commons in 1828 for County Clare for a seat vacated by William Vesey Fitzgerald, another supporter of the Catholic Association. After O'Connell won election, he was unable to take his seat as Members of Parliament had to take the Oath of Supremacy, which was incompatible with Catholicism. The Prime Minister, the Duke of Wellington, and the Home Secretary, Sir Robert Peel, even though they opposed Catholic participation in Parliament, saw that denying O'Connell his seat would cause outrage and could lead to another rebellion or uprising in Ireland, which was about 85% Catholic. Peel and Wellington managed to convince George IV that Catholic emancipation and the right of Catholics and Presbyterians and members of all Christian faiths other than the established Church of Ireland to sit in Parliament needed to be established; with the help of the Whigs, it became law in 1829. However, the Emancipation Act was not made retrospective, meaning that O'Connell had either to seek re-election or to attempt to take the oath of supremacy. When O'Connell attempted to take his seat without taking the oath of supremacy, Solicitor-General Nicholas Conyngham Tindal moved that his seat be declared vacant and another election ordered; O'Connell was elected unopposed on 30 July 1829. He took his seat when Parliament resumed in February 1830; as such he was denied the achievement of being the first Roman Catholic to take advantage of the Emancipation Act and sit in Parliament.

Ironically, considering O'Connell's dedication to peaceful methods of political agitation, his greatest political achievement ushered in a period of violence in Ireland. There was an obligation for those working the land to support the established Church (i.e., the Church of Ireland) by payments known as tithes. The fact that the vast majority of those working the land were Catholic tenant farmers, supporting a minority religion, had been causing tension for some time. An initially peaceful campaign of non-payment turned violent in 1831 when the newly founded Irish Constabulary were used to seize property in lieu of payment resulting in the Tithe War of 1831–36. Although opposed to the use of force, O'Connell successfully defended participants in the battle of Carrickshock and all the defendants were acquitted. Nonetheless O'Connell rejected Sharman Crawford's call for the complete abolition of tithes in 1838, as he felt he could not embarrass the Whigs (the Lichfield house compact secured an alliance between Whigs, radicals and Irish MPs in 1835). In 1841, Daniel O'Connell became the first Roman Catholic Lord Mayor of Dublin since the reign of King James II of England and Ireland and VII of Scotland, who was the last Roman Catholic monarch in the U.K.

Once Catholic Emancipation was achieved, O'Connell campaigned for Repeal of the Act of Union, which in 1801 had merged the Parliaments of the Kingdom of Great Britain and the Kingdom of Ireland to form the United Kingdom of Great Britain and Ireland. In order to campaign for Repeal, O'Connell set up the Repeal Association. He argued for the re-creation of an independent Kingdom of Ireland to govern itself, with Queen Victoria as the Queen of Ireland. To push for this, he held a series of "Monster Meetings" throughout much of Ireland outside the Protestant and Unionist-dominated province of Ulster. They were so called because each was attended by around 100,000 people. These rallies concerned the British Government and then Prime Minister, Sir Robert Peel, banned one such proposed monster meeting at Clontarf, County Dublin, just outside Dublin City. This move was made after the biggest monster meeting was held at Tara.

Tara held great significance to the Irish population as it was the historic seat of the High Kings of Ireland. Clontarf was symbolic because of its association with the Battle of Clontarf in 1014, when the Irish King Brian Boru broke Viking power in Ireland. Despite appeals from his supporters, O'Connell refused to defy the authorities and he called off the meeting, as he was unwilling to risk bloodshed, and had no others. He was arrested, charged with conspiracy, and sentenced to a year's imprisonment and a fine of £2,000, although he was released after three months by the British House of Lords. Having deprived himself of his most potent weapon, the monster meeting, O'Connell, his health failing, had no plan for future action, and dissension broke out in the Repeal Association.

O'Connell died of softening of the brain (cerebral softening) in 1847 in Genoa, Italy, while on a pilgrimage to Rome at the age of 71, his term in prison having seriously weakened him. According to his dying wish, his heart was buried in Rome and the remainder of his body in Glasnevin Cemetery in Dublin, beneath a round tower. His sons are buried in his crypt.

O'Connell's philosophy and career have inspired leaders all over the world, including Mahatma Gandhi (1869 – 1948) and Martin Luther King (1929 – 1968). He was told by William Makepeace Thackeray (1811 – 1863) "you have done more for your nation than any man since Washington ever did." William Gladstone (1809 – 1898) described him as "the greatest popular leader the world has ever seen." Honoré de Balzac (1799 – 1850) wrote that "Napoleon and O'Connell were the only great men the 19th century had ever seen." Jean-Henri Merle d'Aubigné (1794 – 1872) wrote that "the only man like Luther, in the power he wielded was O'Connell." William Grenville (1759 – 1834) wrote that "history will speak of him as one of the most remarkable men that ever lived."

O'Connell is known in Ireland as "The Liberator" or "The Great Emancipator" for his success in achieving Catholic Emancipation. O'Connell admired Latin American liberator Simón Bolívar, and one of his sons, Morgan O'Connell, was a volunteer officer in Bolívar's army in 1820, aged 15.

The principal street in the centre of Dublin, previously called Sackville Street, was renamed O'Connell Street in his honour in the early 20th century after the Irish Free State came into being. His statue (made by the sculptor John Henry Foley, who also designed the sculptures of the Albert Memorial in London) stands at one end of the street, with a statue of Charles Stewart Parnell at the other end. The main street of Limerick is also named after O'Connell, also with a statue at the end (in the centre of The Crescent). O'Connell Streets also exist in Ennis, Sligo, Kilkee, Clonmel, Waterford, Melbourne, Sydney and North Adelaide. There is a statue honouring O'Connell outside St Patrick's Cathedral in Melbourne, Australia, as until the 1950s, the Archdiocese of Melbourne was almost entirely made up of Irish immigrants or Australians of Irish descent. There is a museum commemorating him in Derrynane House, near the village of Derrynane, County Kerry, which was once owned by his family. He was a member of the Literary Association of the Friends of Poland as well.

In 1802 O'Connell married his third cousin, Mary O'Connell. They had four daughters (three surviving), Ellen (b. 1805), Catherine (1808), Elizabeth (1810), and Rickard (1815) and four sons. The sons — Maurice (1803), Timothy James (1804), John (1810), and Daniel (1816) — all sat in Parliament.

O'Connell assisted his younger son, Daniel junior, to acquire the Phoenix brewery in James's Street, Dublin in 1831. The brewery produced a brand known as "O'Connell's Ale" and enjoyed some popularity. By 1832, O'Connell was forced to state that he would not be a political patron of the brewing trade or his son's company, until he was no longer a Member of Parliament, particularly because O'Connell and Arthur Guinness were political enemies. Guinness was the "moderate" liberal candidate, O'Connell was the "radical" liberal candidate. The rivalry caused dozens of Irish firms to boycott Guinness during the 1841 Repeal election. It was at this time that Guinness was accused of supporting the "Orange system", and its beer was known as "Protestant porter". When the O'Connell family left brewing, the rights to "O'Connell Dublin Ale" was sold to John D'Arcy. The brewing business proved to be unsuccessful though, and after a few years was taken over by the manager, John Brennan, while Daniel junior embraced a political career. Brennan changed the name back to the Phoenix Brewery but continued to brew and sell O'Connell's Ale. When the Phoenix Brewery was effectively closed after being absorbed into the Guinness complex in 1909, the brewing of O'Connell's Ale was carried out by John D'Arcy and Son Ltd at the Anchor Brewery in Usher Street. In 1926, D'Arcy's ceased trading and the firm of Watkins Jameson and Pim carried on the brewing until they too succumbed to the pressures of trying to compete with Guinness.

Daniel junior was the committee chairman of the licensed trade association of the period and gave considerable and valuable support to Daniel O'Connell in his public life. Some time later a quarrel arose and O'Connell turned his back on the association and became a strong advocate of temperance. During the period of Fr. Matthew's total abstinence crusades many temperance rallies were held, the most notable being a huge rally held on St. Patrick's Day in 1841. Daniel O'Connell was a guest of honour at another such rally held at the Rotunda hospital.

Michael Doheny, in his The Felon's Track, says that the very character of Emancipation has assumed an "exaggerated and false guise" and that it is an error to call it emancipation. He went on, that it was neither the first nor the last nor even the most important in the concessions, which are entitled to the name of emancipation, and that no one remembered the men whose exertions "wrung from the reluctant spirit of a far darker time the right of living, of worship, of enjoying property, and exercising the franchise." Doheny's opinion was, that the penalties of the "penal laws" had been long abolished, and that barbarous code had been compressed into cold and stolid exclusiveness and yet Mr. O'Connell monopolised its entire renown. The view put forward by John Mitchel, also one of the leading members of the Young Ireland movement, in his "Jail Journal" was that there were two distinct movements in Ireland during this period, which were rousing the people, one was the Catholic Relief Agitation (led by O'Connell), which was both open and legal, the other was the secret societies known as the Ribbon and White-boy movements. The first proposed the admission of professional and genteel Catholics to Parliament and to the honours of the professions, all under British law — the other, originating in an utter horror and defiance of British law, contemplated nothing less than a social, and ultimately, a political revolution. According to Mitchel, for fear of the latter, Great Britain with a "very ill grace yielded to the first". Mitchel agrees that Sir Robert Peel and the Duke of Wellington said they brought in this measure, to avert civil war; but says that "no British statesman ever officially tells the truth, or assigns to any act its real motive." Their real motive was, according to Mitchel, to buy into the British interests, the landed and educated Catholics, these "Respectable Catholics" would then be contented, and "become West Britons" from that day.

A critic of violent insurrection in Ireland, O'Connell once said that "the altar of liberty totters when it is cemented only with blood," and yet as late as 1841, O'Connell had whipped his MPs into line to keep the "Opium War" going in China. The Tories at this time, had proposed a motion of censure over the War, and O'Connell had to call upon his MPs to support the Whig Government, as a result of this intervention, the Government was saved.

Politically, he focused on parliamentary and populist methods to force change and made regular declarations of his loyalty to the British Crown. He often warned the British Establishment that if they did not reform the governance of Ireland, Irishmen would start to listen to the "counsels of violent men". Successive British governments continued to ignore this advice, long after his death, although he succeeded in extracting by the sheer force of will and the power of the Catholic peasants and clergy much of what he wanted, i.e., eliminating disabilities on Roman Catholics; ensuring that lawfully elected Roman Catholics could serve their constituencies in the British Parliament (until the Irish Parliament was restored); and amending the Oath of Allegiance so as to remove clauses offensive to Roman Catholics who could then take the Oath in good conscience.

Although a native speaker of the Irish language, O'Connell encouraged Irish people to learn English in order to better themselves. Although he is best known for the campaign for Catholic Emancipation; he also supported similar efforts for Irish Jews. At his insistence, in 1846, the British law "De Judaismo", which prescribed a special dress for Jews, was repealed. O'Connell said: "Ireland has claims on your ancient race, it is the only country that I know of unsullied by any one act of persecution of the Jews".