Tilghman was born on the family plantation, The Hermitage, near Centreville in Queen Anne's County, Maryland.

His grandfather, Richard Tilghman (1626–1675) had been a surgeon in the British navy and established the family plantation at the Hermitage.

He was the chairman of the Committee of Safety, president of the revolutionary assembly known as the Annapolis Convention, and the head of the Maryland delegation to the Continental Congress.

He voted for its final approval but was replaced in the Congress by Charles Carroll of Carrollton before a copy was signed.

Tilghman had to return home to preside over a longer session of the Annapolis Convention that established a new government for Maryland.

Besides being president of the Convention, he headed the committee that drafted the Charter of Rights and Plan of Government that became Maryland's constitution.