In 1847 recieved his law degree.
He was named Intendente (governor) of the Province of Colchagua in 1850. Strongly Liberal in his politics, he participated in the revolt in 1851 against the election of President Manuel Montt Torres. As a result, he was exiled to Peru until 1853.
Returning home, Domingo Santa Maria practiced his profession, as well as being a journalist and publishing studies of Chilean history. In 1858 his political activities again brought exile for four years. He returned under an amnesty law in 1862.
During the next four years, Santa Maria was a member of the appeals court of Santiago and the Supreme Court. He also was minister of justice and public instruction for some months. During the 1865-1866 war with Spain, he had diplomatic assignments. After that war, he again served on the Supreme Court and was minister of foreign relations, interior, and war and navy.
Domingo Santa Maria was the government’s candidate for president in 1881. General Manuel Baquedano, victor in the War of the Pacific against Peru and Bolivia, returned home amidst great acclaim and was put forward by the Conservatives as their candidate. However, all Liberal factions, as well as other groups, rallied behind Santa Maria, fearing that Baquedano’s selection might bring militarism.
After leaving the presidency, Domingo Santa Maria was elected to the Senate in 1888. When he died, he was president of the Senate.