In 1618 his History of Tithes appeared. Although it was only published after submission to the censor and licensing, this dissertation on the historical basis of the tithe system caused anxiety among the bishops and provoked the intervention of the king. The author was summoned before the privy council and compelled to retract his opinions. His work was suppressed and he was forbidden to reply to anyone who might come forward to answer it.

This all seems to have caused Selden's entry into politics. Although he was not in Parliament, he was the instigator and perhaps the draughtsman of the protestation on the rights and privileges of the House affirmed by the House of Commons on 18 December 1621. He and several others were imprisoned, at first in the Tower and later under the charge of Sir Robert Ducie, sheriff of London. During his brief detention, he occupied himself in preparing an edition of Eadmer's History from a manuscript lent to him by his host or jailor, which he published two years afterwards.

In 1623 he was returned to the House of Commons for the borough of Lancaster, and sat with John Coke, William Noy and John Pym on Sergeant Glanville's election committee. He was also nominated reader of Lyon's Inn, an office he declined to undertake. For this the benchers of the Inner Temple fined him £20 and disqualified him from being one of their number. Nevertheless, after a few years, he became a master of the bench. In the first parliament of Charles I (1625), it appears from the "returns of members" printed in 1878 that, contrary to the assertion of all his biographers, he had no seat. In Charles's second parliament (1626) he was elected for Great Bedwyn in Wiltshire, and took a prominent part in the impeachment of George Villiers, 1st Duke of Buckingham. In the following year, in Darnell's Case (the Five Knights' Case), he was counsel for Sir Edmund Hampden in the Court of King's Bench.

In 1628 he was returned to the third parliament of Charles for Ludgershall, Wiltshire, and was involved in drawing up and carrying the Petition of Right. In the session of 1629 he was one of the members responsible for the tumultuous passage in the House of Commons of the resolution against the illegal levy of tonnage and poundage, and, along with Sir John Eliot, Denzil Holles, Long, Valentine, William Strode, and the rest, he was sent back to the Tower. There he remained for eight months, deprived for a part of the time of the use of books and writing materials. He was then removed, under less rigorous conditions, to the Marshalsea, until Archbishop Laud arranged for him to be freed. Some years before he had been appointed steward to the Earl of Kent, to whose seat, Wrest in Bedfordshire, he now retired.

He was not elected to the Short Parliament of 1640; but to the Long Parliament, summoned in the autumn, he was returned without opposition for Oxford University. He opposed the resolution against episcopacy which led to the exclusion of the bishops from the House of Lords, and printed an answer to the arguments used by Sir Harbottle Grimston on that occasion. He joined in the protestation of the Commons for the maintenance of the Protestant religion according to the doctrines of the Church of England, the authority of the crown, and the liberty of the subject. He was equally opposed to the court on the question of the commissions of lieutenancy of array and to the parliament on the question of the militia ordinance. In the end he supported Parliament against King Charles, because (he said) he was certain the latter was acting illegally, while he wasn't certain about the former.

In 1643 he participated in the discussions of the Westminster Assembly, where his Erastian views were opposed by George Gillespie. Selden's allies included Thomas Coleman, John Lightfoot, and Bulstrode Whitelocke.

He was appointed shortly afterwards keeper of the rolls and records in the Tower. In 1645 he was named one of the parliamentary commissioners of the admiralty, and was elected master of Trinity Hall, Cambridge — an office he declined to accept. In 1646 he subscribed the Solemn League and Covenant, and in 1647 was voted £5000 by the parliament as compensation for his pains under the monarchy.

After the death of the Earl of Kent in 1639 Selden lived permanently under the same roof with the earl's widow, the former Elizabeth Talbot. It is believed that he married her, although their marriage does not seem to have ever been publicly acknowledged. He died at Friary House in Whitefriars, and was buried in the Temple Church, London. His tomb is today clearly visible through glass plates in the floor of this church. Furthermore, he is commemorated by a monumental inscription on the south side of the Temple Church. More than two centuries after his death, in 1880, a brass tablet was erected to his memory by the benchers of the Inner Temple in the parish church of West Tarring.

It was as a prolific scholar and writer that Selden won his reputation. The early books were on English history.

In 1610 three of his works came out: England's Epinomis and Jani Anglorum; Facies Altera, which dealt with the progress of English law down to Henry II; and The Duello, or Single Combat, in which he traced the history of trial by battle in England from the Norman Conquest. In 1613 he supplied a series of notes, including quotations and references, to the first eighteen cantos of Michael Drayton's Poly - Olbion. In 1614 he published Titles of Honor [sic], which, in spite of defects and omissions, remained a comprehensive reference work for centuries. It earned for Selden the praise "monarch of letters" from his friend Ben Jonson.

In 1615, the Analecton Anglobritannicon, an account of the civil administration of England before the Norman Conquest, written in 1607, was published; its title and argument imitated the Franco - Gallia of François Hotman. In 1616 appeared notes on John Fortescue's De laudibus legum Angliae and Ralph de Hengham's Summae magna et parva.

In 1618 his controversial History of Tithes was published. A first sign of the coming storm was the 1619 book controverting Selden in an appendix, Sacrilege Sacredly Handled by James Sempill. Selden hit back, but was soon gagged. The churchmen Richard Tillesley (1582 – 1621) (Animadversions upon M. Seldens History of Tithes, 1619) and Richard Montagu (Diatribae upon the first part of the late History of Tithes, 1621) attacked the work. There were further replies by William Sclater (The Quaestion of Tythes Revised, 1623), and by Stephen Nettles (Answer to the Jewish Part of Mr. Selden's History of Tithes 1625). In it Selden tried to demonstrate that tithing depended on the civil law, rather than canon law. He also made much of the complexities of the ancient Jewish customs on tithes.

In 1623 he produced an edition of Eadmer's Historia Novarum. It was notable for including in appendices information from the Domesday Book, which at the time had not been published and could only be consulted in the original at Westminster, on the payment of a fee.

He published in 1642 Privileges of the Baronage of England when they sit in Parliament and Discourse concerning the Rights and Privileges of the Subject. In 1652 he wrote a preface and collated some of the manuscripts for Sir Roger Twysden's Historiae Anglicae scriptores decem.

In 1617 his De diis Syriis was issued, and immediately established him fame as an orientalist. It is remarkable for its early use of the comparative method, on Semitic mythology. Also in 1642 he published a part of the Arabic chronicle of Patriarch Eutychius of Alexandria, under the title Eutychii Aegyptii, Patriarchae Orthodoxorum Alexandrini, ... ecclesiae suae origines. This mattered for the discussion in it of the absence in Alexandria of the distinction between priests and bishops, a burning issue in the debate at the time in the Church of England.

In 1628, at the suggestion of Sir Robert Cotton, Selden compiled, with the assistance of two other scholars, Patrick Young and Richard James, a catalog of the Arundel marbles.

He employed his leisure at Wrest in writing De successionibus in bona defuncti secundum leges Ebraeorum and De successione in pontificatum Ebraeorum, published in 1631.

During the progress of the constitutional conflict, he was absorbed in research, publishing De jure naturali et gentium juxta disciplinam Ebraeorum in 1640. It was a contribution to the theorizing of the period on natural law. In the words of John Milton, this "volume of naturall & national laws proves, not only by great authorities brought together, but by exquisite reasons and theorems almost mathematically demonstrative, that all opinions, yea errors, known, read, and collated, are of main service & assistance toward the speedy attainment of what is truest." It develops into a theory of international law, taking as its basis the Seven Laws of Noah.

In 1644, he published Dissertatio de anno civili et calendario reipublicae Judaicae, in 1646 his treatise on marriage and divorce among the Jews entitled Uxor Ebraica, and in 1647 the earliest printed edition of the old English law - book Fleta. In 1650 Selden began to print the trilogy he planned on the Sanhedrin, as the first part of De synedriis et prefecturis juridicis veterum Ebraeorum through the press, the second and third parts being severally published in 1653 and 1655. The aim of this work was to counter the use the Presbyterians, in particular, made of arguments and precedents drawn from Jewish tradition; it was a very detailed study aimed at refuting such arguments, and pointing out the inherent flexibility of the actual tradition that was being cited.

He seems to have inclined towards the court rather than the popular party, in the early 1630s, and even to have secured the personal favor of the king. To him in 1635 he dedicated his Mare clausum, and under the royal patronage it was put forth as a kind of state paper.

It had been written sixteen or seventeen years before, but James I had prohibited its publication for political reasons; hence it appeared a quarter of a century after Grotius's The Free Sea (Mare liberum), to which it was intended to be a rejoinder, and the pretensions advanced in which on behalf of the Dutch fishermen to poach in the waters off the English coasts, it was its purpose to explode. The fact that Selden was not retained in the great case of ship money in 1637 by John Hampden, the cousin of his former client, may be accepted as additional evidence that his zeal in the popular cause was not so warm and unsuspected as it had once been.

His last publication was a vindication of himself from certain charges advanced against him and his Mare clausum around 1653 by Theodore Graswinckel, a Dutch jurist.

Several of Selden's minor works were printed for the first time after his death, and a collective edition of his writings was published by David Wilkins in 3 volumes folio in 1725, and again in 1726. Table Talk, for which he is perhaps best known, did not appear until 1689. It was edited by his amanuensis, Richard Milward, who affirms that "the sense and notion is wholly Selden's," and that "most of the words" are his also. Its genuineness has sometimes been questioned.

Selden arrived at an Erastian position in church politics. He also believed in free will, which was inconsistent with Calvinism.

He was skeptical of the legend of King Arthur as it had grown up, but believed Arthur had existed. The Druids, he commented on Poly - Olbion, were ancient and presumed esoteric thinkers. The popular image of a Druid descends via a masque of Inigo Jones from a reconstruction by Selden, based (without good foundations) on ancient German statuary.

According to the Encyclopedia of Historians and Historical Writing, he "played a role of fundamental importance in the transition of English historical writing from a medieval antiquarianism to a more modern understanding of the scope and function of history than had ever before been expressed in Renaissance England". His reputation lasted well, with Mark Pattison calling him "the most learned man, not only of his party, but of Englishmen".

By about 1640, Selden's views (with those of Grotius) had a large impact on the Great Tew circle around Lucius Cary, 2nd Viscount Falkland: William Chillingworth, Dudley Digges, Henry Hammond. It was in this milieu that Selden met and befriended Thomas Hobbes. They had much in common, in political thought, but the precise connections have not been clarified.

Richard Cumberland followed Selden over both Grotius and Hobbes on natural law. Selden contested the scholastic position, after Cicero, that "right reason" could by its dictates alone generate obligation, by claiming that a formal obligation required a superior in authority. In his De legibus Cumberland rejects Selden's solution by means of the Noahide laws, in De jure naturali, in favour of Selden's less developed alternate solution. The latter is more orthodox for a Thomist, an intellectus agens as a natural faculty in the rational soul, by the mediation of which divine intellect can intervene directly with individuals. Matthew Hale tried to merge the theory of Grotius on property with Selden's view on obligation. Cumberland and Hale both belonged to a larger group, followers in a broad sense of Selden, with backgrounds mostly of Cambridge and the law, comprising also Orlando Bridgeman, Hezekiah Burton, John Hollings, Richard Kidder, Edward Stillingfleet, John Tillotson, and John Wilkins.

Giambattista Vico called Grotius, Selden and Samuel Pufendorf the "three princes" of the "natural right of the gentes". He went on to criticize their approach foundationally. In his Autobiography he specifies that they had conflated the natural law of the "nations", based on custom, with that of the philosophers, based on human abstractions. Isaiah Berlin comments on Vico's admiration for Grotius and Selden.