In 1868 Fitzmaurice was elected unopposed to Parliament for the family constituency of Calne, a seat he would hold until 1885, and served as Parliamentary Private Secretary to Robert Lowe, Chancellor of the Exchequer and later Home Secretary, from 1872 to 1874, when the Liberals fell from office. He was appointed Commissioner at Constantinople in 1880, overseeing the reorganisation of the European provinces of the Ottoman Empire under the Berlin Treaty of 1878. However, his ambitious plans and ideas for the area were never implemented. The Liberals had returned to power in 1880, and in 1883 Gladstone appointed Fitzmaurice Under-Secretary of State for Foreign Affairs, succeeding Sir Charles Dilke, which he remained until the fall of the Liberal Government in 1885. The Calne constituency he had represented since 1868 was abolished in 1885, and he was instead chosen as the Liberal candidate for the Glasgow constituency of Blackfriars and Hutchesontown. However, illness forced Fitzmaurice into semi-retirement before the elections. He returned to public life in 1887 but was unsuccessful in his attempts to return to Parliament when he stood for Deptford in the 1892 general election and for Cricklade in the 1895 general election. However, in 1898 he was successfully returned for Cricklade in a by-election, a constituency he would represent until 1906. When the Liberals came to power in late 1905 under Sir Henry Campbell-Bannerman, Fitzmaurice was appointed to his old post of Under-Secretary of State for Foreign Affairs, but to the surprise of many he was overlooked for a Cabinet post. He was in fact offered the position of Foreign Secretary should Sir Edward Grey refuse it. Fitzmaurice chose not to stand in the 1906 General Election, and was instead raised to the peerage as Baron Fitzmaurice, of Leigh in the County of Wiltshire. He remained at the Foreign Office after Asquith became Prime Minister in April 1908 and was admitted to the Privy Council the same month. In October 1908 he was appointed Chancellor of the Duchy of Lancaster, with a seat in the Cabinet. However, a recurrence of his earlier illness forced him to resign the following year, marking the end of his political career. Following Asquith's ascension to the premiership, Fitzmaurice was critical of what he saw as "the Liberals' aimless drift in domestic politics," although following his resignation he was "anxious to dispel rumours that his resignation was caused by a rift with Asquith or misgivings over Lloyd George's controversial 'People's Budget.'"
Lord Fitzmaurice married Caroline FitzGerald, daughter of William John FitzGerald of Connecticut, in 1889. Their marriage was annulled in 1894 and produced no children. He died in June 1935, two days after his 89th birthday. The title became extinct on his death.
