He move to Martha's Vineyard with his father around 1641 and there became interested in the welfare of the Native Americans on the island.
Unfortunately, the younger Mayhew was lost at sea during a voyage back to England but the missionary cause was upheld by his father.
Initially, Matthew Mayhew, the oldest grandson, succeeded his father and grandfather as head missionary of the island.
He studied at Harvard College, Cambridge, mastered the Wôpanâak language, and wrote a tract explaining the third generation of the Vineyard mission: A brief narrative of the success which the Gospel Hath Had, among the Indians, of Martha's Vineyard (1694): he discusses the language, political system and religion of the Wampanoags and includes several letters by missionaries from other parts of New England.
The grandson, an astute observer, would forsake titles such as “Governor for Life” and get himself appointed Chief Magistrate — a position in which he would be able to exercise nearly as total an authority as had his grandfather without nearly so much of a hassle.