He was elected as a Jacksonian Democrat to the United States Senate and served from March 4, 1825, succeeding his fellow Federalist John Elliott.

[5] On March 9, 1829, he resigned from the Senate to accept the position of Attorney General in the Cabinet of President Andrew Jackson.

His first assignment was to prosecute former Treasury Fourth Auditor Tobias Watkins for embezzlement of public funds.

Berrien's views on sectional issues hardened during his tenure in the Senate and he became aligned with the short-lived Southern Rights Party formed to oppose the Compromise of 1850 and the Wilmot Proviso.

During the 1820s, Berrien was a member of the prestigious society, Columbian Institute for the Promotion of Arts and Sciences, which counted among its members presidents Andrew Jackson and John Quincy Adams and many prominent men of the day, including well-known representatives of the military, government service, medical and other professions.

The Georgia Historical Society holds a substantial collection of Berrien papers (including important material relating to the Petticoat affair).