O'Donohoe ran unsuccessfully for the Legislative Assembly of Ontario in the 1871 election and in an 1872 by-election. He ran for the House of Commons of Canada in the 1872 federal election for the riding of Toronto East and was defeated. He was elected in the 1874 election but was unseated on petition in November 1874 and lost the resulting 1875 by-election. He was appointed to the Senate on the advice of John Alexander Macdonald in May 1882 representing the senatorial division of Erie, Ontario. A Liberal-Conservative, he served 21 years until his death in 1902.
