[1] Gershom's father, Isaac Mendes Seixas (1709-1780), was a merchant born in Lisbon, Portugal, who first emigrated to Barbados before coming to the British colonies, living in New York City around 1730 and moving to Newport, Rhode Island, around 1765.

In all, he had fifteen children, of whom the most famous would be David Seixas, who established the Pennsylvania Institution for the Deaf and Dumb in Philadelphia, and was among the first to discover efficient ways of burning anthracite coal.

In 1766, Gershom Mendes Seixas became the leader of Shearith Israel, New York City's first and oldest Spanish and Portuguese Sephardi congregation, and remained its minister for about a half century.

As the British fleet approached New York Bay in August, 1776, Seixas preached an emotional sermon in English, warning that that day's services might be the last held in the historic edifice.

Many important politicians attended the synagogue's dedication, including the governor of Pennsylvania, and Seixas invoked "the blessings of Almighty God on the Members of these States in Congress assembled and on his Excellency George Washington, Commander-General of these Colonies".

[5] Mendes Seixas enjoyed the friendship of many religious leaders (although before the Revolutionary War, many held Tory sympathies) and frequently was asked to speak to Christian congregations.

One of his descendants was Everett Seixas, a combat soldier in the 80th Infantry Division of the United States Army during World War II who was killed in action in the Battle of the Bulge.