Blake was called to the bar in 1856 and created a queen's counsel in 1864. In 1867 he was elected to both the Ontario Legislative Assembly and the Canadian House of Commons as a Liberal. After the abolition of dual representation caused him to resign as prime minister of Ontario, he became minister of justice in Alexander Mackenzie's cabinet (1875–77), where he helped draft the constitution of the Supreme Court of Canada and determine the powers of the governor-general. In 1880 he succeeded Mackenzie to lead for seven years what was then the opposition Liberal Party (Liberal Party of Canada), resigning after two defeats in general elections.

Blake left the party and Canadian politics altogether in 1890, after a disagreement with his party over trade policy. He then entered Irish politics, sitting as an Irish Nationalist member for South Longford in the British House of Commons (1892–1907). He helped draft the 1893 Home Rule Bill and advised on the financial relationship between Britain and Ireland. He also helped raise funds in Canada and the United States for the Irish Parliamentary Party.