In 1816, Holmes was one of the commissioners under the Treaty of Ghent to divide the islands of Passamaquoddy Bay between the United States and Great Britain.

He was also appointed by the legislature to organize state prisons and revise the Massachusetts criminal code.

During the 16th Congress, Holmes served as chairman of the Committee on Expenditures in the Department of State.

Jefferson himself rejected the compromise: But this momentous question, like a fire bell in the night, awakened and filled me with terror.

(...) An abstinence too from this act of power would remove the jealousy excited by the undertaking of Congress, to regulate the condition of the different descriptions of men composing a state.

Holmes was again elected to the Senate to fill the vacancy caused by the resignation of Albion Parris, serving from January 15, 1829, to March 3, 1833.

In 1841, Holmes was appointed as the United States Attorney for the District of Maine, a post he held until his death in Portland on July 7, 1843.