Holmes was born in Kingston, Massachusetts, on March 14, 1773.

He attended the Kingston public schools; graduated from Rhode Island College now Brown University located in Providence, Rhode Island in 1796 where he studied law, he was admitted to the bar in 1799, and settled in Alfred, Maine, then a district of Massachusetts.

He practised with success. he also engaged in literary pursuits. He was a member of the Massachusetts house of representatives from 1802 until 1803, and took an active part in the debates.

He was elected to the Massachusetts General Court in 1802, 1803, and 1812.

He was elected to the State senate in 1813 and served until 1817, he was one of the commissioners under the treaty of Ghent to divide the islands of Passamaquoddy Bay between the United States and Great Britain in 1816, when he was chosen to congress as a Democrat from Massachusetts, and served until the admission of Maine as a state in 1820.

He was a member of the convention to form a state constitution, and chairman of the committee that drafted it.

In 1820 he was elected a senator to congress from Maine, and re-elected for a full term the following year.

He was appointed by the legislature a commissioner to devise and report a system of government for the state prison and to revise the criminal code of the state.

On the resignation of Albion K. Parris in 1827, he was again elected to the United States senate, serving untill 1833.

In 1835 until 1838 he was a member of the state house of representatives and in 1841 he was appointed United States attorney for the district of Maine.

He published "The Statesman, or Principles of Legislation and Law" (Augusta, 1840).

He died in Portland, Maine on July 7, 1848 and is buried in a private tomb of Cotton Brooks, Eastern Cemetery.