At the age of 16 Grote joined his father's bank in London and worked in it until 1843, using his spare time to perfect his command of Greek and to learn German, economics, and philosophy. From 1832 to 1841 he was a member of Parliament for the City of London.

Having already published works on contemporary politics and philosophy, Grote devoted himself entirely to the History of Greece, which was published in 12 volumes between 1846 and 1856; it ended with the events of 301 BC. It was quickly recognized (in the original or in translation) as the best Greek history in any language, and its authority remained unchallenged for almost half a century. Grote, it may be noted, never visited Greece.

In 1849 Grote reassumed an earlier active interest in University College, London. He became its treasurer in 1860 and its president in 1868. From 1862 until his death he was also vice-chancellor of the University of London. He refused a peerage that Prime Minister William Gladstone offered him in 1869. Grote was buried in Westminster Abbey.