Mayhew's father was a Congregational missionary to Indians, whereas Jonathan served for nineteen years as minister of the West Congregational Church of Boston, which the orthodox suspected of liberal tendencies. Their suspicion was confirmed when Dr. Gay of Hingham preached the ordination sermon.

A successor described Jonathan Mayhew as "the first preacher in Boston of an antitrinitarian God, the most clerical asserter in America of civil and religious affairs...who broke down the partition wall between secular and religious affairs."