In Palestine, he first worked in agriculture, picking oranges. In 1909 he volunteered with HaShomer, a force of volunteers who helped guard isolated Jewish agricultural communities. On November 7, 1911, Ben Gurion arrived in Thessaloniki in order to learn Turkish for his law studies. The city, which had a large Jewish community, impressed Ben Gurion who called it "a Jewish city that has no equal in the world." He also realized there that "the Jews were capable of all types of work," from rich businessmen and professors, to merchants, craftsmen and porters. In 1912, he moved to Constantinople (now Istanbul), the then Ottoman capital, to study law at Istanbul University together with Ben-Zvi, and adopted the Hebrew name Ben-Gurion, after the medieval historian Yosef ben Gurion. He also worked as a journalist. In 1915, Ben-Gurion and Ben-Zvi were expelled from Palestine, still under Ottoman rule, for their political activities.

Settling in New York City in 1915, he met Russian-born Paula Munweis. They were married in 1917, and had three children. He joined the British army in 1918 as part of the 38th Battalion of the Jewish Legion (following the Balfour Declaration in November 1917). He and his family returned to Palestine after World War I following its capture by the British from the Ottoman Empire.

After the death of theorist Ber Borochov, the left-wing and right-wing of Poale Zion split in 1919 with Ben-Gurion and his friend Berl Katznelson leading the right faction of the Labor Zionist movement. The Right Poale Zion formed Ahdut HaAvoda with Ben-Gurion as leader in 1919. In 1920 he assisted in the formation and subsequently became general secretary of the Histadrut, the Zionist Labor Federation in Palestine.

In 1930, Hapoel Hatzair (founded by A.D. Gordon in 1905) and Ahdut HaAvoda joined forces to create Mapai, the more right-wing Zionist labor party (it was still a left-wing organization, but not as far left as other factions) under Ben-Gurion's leadership. The left-wing of Labour Zionism was represented by Mapam. Labor Zionism became the dominant tendency in the World Zionist Organization and in 1935 Ben-Gurion became chairman of the executive committee of the Jewish Agency for Palestine, a role he kept until the creation of the state of Israel in 1948.

During the 1936–1939 Arab revolt in Palestine, Ben-Gurion instigated a policy of restraint ("Havlagah") in which the Haganah and other Jewish groups did not retaliate for Arab attacks against Jewish civilians, concentrating only on self-defense. In 1937, the Peel Commission recommended partitioning Palestine into Jewish and Arab areas and Ben-Gurion supported this policy. This led to conflict with Ze'ev Jabotinsky who opposed partition and as a result Jabotinsky's supporters split with the Haganah and abandoned Havlagah.

The Ben Gurion House, where he lived from 1931 on, and for part of each year after 1953, is now a museum in Tel Aviv.

Ben-Gurion recognized the strong attachment of Palestinian Arabs to the land but hoped that this would be overcome in time. Nahum Goldman, president of the World Jewish Congress, wrote that in a conversation about "the Arab problem" in 1956, Ben-Gurion stated: "Why should the Arabs make peace? If I was an Arab leader I would never make terms with Israel. That is natural: we have taken their country ... There has been anti-Semitism, the Nazis, Hitler, Auschwitz, but was that their fault? They only see one thing: we have come here and stolen their country. Why should they accept that? They may perhaps forget in one or two generations' time, but for the moment there is no chance. So it is simple: we have to stay strong and maintain a powerful army." Goldman criticized Ben-Gurion for what he viewed as Ben-Gurion's confrontational approach to the Arab world. Goldman wrote that "Ben-Gurion is the man principally responsible for the anti-Arab policy, because it was he who moulded the thinking of generations of Israelis." The view that Ben-Gurion's assessment of Arab feelings led him to emphasize the need to build up Jewish military strength is supported by Simha Flapan, who quoted Ben-Gurion as stating in 1938: "I believe in our power, in our power which will grow, and if it will grow agreement will come..."

The British 1939 White paper stipulated that Jewish immigration to Palestine was to be limited to 15,000 a year for the first five years, and would subsequently be contingent on Arab consent. Restrictions were also placed on the rights of Jews to buy land from Arabs. After this Ben-Gurion changed his policy towards the British, stating: "Peace in Palestine is not the best situation for thwarting the policy of the White Paper". Ben-Gurion believed a peaceful solution with the Arabs had no chance and soon began preparing the Yishuv for war. According to Teveth 'through his campaign to mobilize the Yishuv in support of the British war effort, he strove to build the nucleus of a "Hebrew army", and his success in this endeavor later brought victory to Zionism in the struggle to establish a Jewish state.'

During the Second World War, Ben-Gurion encouraged the Jews of Palestine to volunteer for the British army. He famously told Jews to "support the British as if there is no White Paper and oppose the White Paper as if there is no war". About 10% of the Jewish population of Palestine volunteered for the British army, including many women. At the same time Ben-Gurion helped the illegal immigration of thousands of European Jewish refugees to Palestine during a period when the British placed heavy restrictions on Jewish immigration.

In 1946 Ben-Gurion agreed that the Haganah could cooperate with Menachem Begin's Irgun in fighting the British. Ben-Gurion initially agreed to Begin's plan to carry out the 1946 King David Hotel bombing, with the intent of embarrassing (rather than killing) the British military stationed there. However, when the risks of mass killing became apparent, Ben-Gurion told Begin to call the operation off; Begin refused.

Illegal Jewish migration led to pressure on the British to either allow Jewish migration (as required by the League of Nations Mandate) or quit - they did the latter in 1948, not changing their restrictions, on the heels of a United Nations resolution partitioning the territory between the Jews and Arabs.

In September 1947 Ben-Gurion reached a status quo agreement with the Orthodox Agudat Yisrael party. He sent a letter to Agudat Yisrael stating that while he is committed to establishing a non-theocratic state with freedom of religion he is promising that the Shabbat would be Israel's official day of rest, that in State provided kitchens there will be access to Kosher food, that every effort will be made to provide a single jurisdiction for Jewish family affairs, and that each sector would be granted autonomy in the sphere of education, provided minimum standards regarding the curriculum are observed. To a large extent this letter (or agreement) provided a framework for religious affairs in Israel (e.g. no civil marriages, just as in Mandate times) and is often a benchmark to which the status is compared.

During the 1948 Arab-Israeli War Ben-Gurion oversaw the nascent state's military operations. During the first weeks of Israel's independence, he ordered all militias to be replaced by one national army, the Israel Defense Forces (IDF). To that end, Ben-Gurion used a firm hand during the Altalena Affair, a ship carrying arms purchased by the Irgun. He insisted that all weapons be handed over to the IDF. When fighting broke out on the Tel Aviv beach he ordered to take it by force and shell the ship. Sixteen Irgun fighters and three IDF soldiers were killed in this battle. Following the policy of a unified military force, he also ordered that the Palmach headquarters be disbanded and its units be integrated with the rest of the IDF, to the chagrin of many of its members.

As head of the Jewish Agency, Ben-Gurion was de-facto leader of Palestine's Jews even before the state was declared. In this position, Ben-Gurion played a major role in the 1948 War and the resulting Palestinian exodus. When the IDF archives and others were opened in the late 1980s, scholars started to reconsider the events and the role of Ben Gurion.

On 14 May, on the last day the British Mandate, Ben-Gurion declared the independence of the state of Israel. In the Israeli declaration of independence, he stated that the new nation would "uphold the full social and political equality of all its citizens, without distinction of race, creed or sex."

After leading Israel during the 1948 Arab-Israeli War, Ben-Gurion was elected Prime Minister of Israel when his Mapai (Labour) party won the largest number of seats in the first national election, held on February 14, 1949. He would remain in that post until 1963, except for a period of nearly two years between 1954 and 1955. As Premier, he oversaw the establishment of the state's institutions. He presided over various national projects aimed at the rapid development of the country and its population: Operation Magic Carpet, the airlift of Jews from Arab countries, the construction of the National Water Carrier, rural development projects and the establishment of new towns and cities. In particular, he called for pioneering settlement in outlying areas, especially in the Negev. Ben-Gurion had a major role in the military operations that led to the Qibya massacre in October, 1953. Later in 1953 he announced his intention to withdraw from government and was replaced by Moshe Sharett, who was elected the second Prime Minister of Israel in January, 1954.

Ben-Gurion returned to office in 1955 assuming the post of Defense Minister and was soon re-elected prime minister. When Ben-Gurion returned to government, Israeli forces responded more aggressively to Palestinian guerilla attacks from Gaza — still under Egyptian rule. The growing cycle of violence led Egypt's President Gamal Abdel Nasser to build up his arms with the help of the Soviet Union. The Israelis responded by arming themselves with help from France. Nasser blocked the passage of Israeli ships through the Red Sea and Suez Canal. In July 1956, America and Britain withdrew their offer to fund the Aswan High Dam project on the Nile and a week later Nasser ordered the nationalization of the French and British controlled Suez Canal. Ben-Gurion collaborated with the British and French to plan the 1956 Sinai War in which Israel stormed the Sinai Peninsula thus giving British and French forces a pretext to intervene in order to secure the Suez Canal. Intervention by the United States and the United Nations forced the British and French to back down and Israel to withdraw from Sinai in return for promises of free navigation through the Red Sea and Suez Canal. A UN force was stationed between Egypt and Israel.

Ben-Gurion stepped down as prime minister for what he described as personal reasons in 1963, and chose Levi Eshkol as his successor. A year later a rivalry developed between the two on the issue of the Lavon Affair. Ben-Gurion broke with the party in June 1965 over Eshkol's handling of the Lavon affair and formed a new party, Rafi which won ten seats in the Knesset. After the Six-Day War, Ben-Gurion was in favour of returning all the occupied territories apart from Jerusalem, the Golan Heights and Mount Hebron.

In 1968, when Rafi merged with Mapai to form the Alignment, Ben-Gurion refused to reconcile with his old party. He favoured electoral reforms in which a constituency-based system would replace what he saw as a chaotic proportional representation method. He formed another new party, the National List, which won four seats in the 1969 election. Ben-Gurion retired from politics in 1970 and spent his last years living in a modest home on the kibbutz.

Ben-Gurion believed that the sparsely populated and barren Negev desert offered a great opportunity for the Jews to settle in Palestine with minimal obstruction of the Arab population. He set a personal example by choosing to settle in kibbutz Sde Boker at the centre of the Negev and established the National Water Carrier to bring water to the area. He saw the struggle to make the desert bloom as an area where the Jewish people could make a major contribution to humanity as a whole.

Ben-Gurion died on 1 December 1973, and is buried alongside his wife Paula at a site in Midreshet Ben-Gurion in the Negev desert.