Cameron was born in Maytown, Pennsylvania, to Charles Cameron and Marth Pfoutz. He was orphaned at nine and later apprenticed to a printer, Andrew Kennedy, editor of the Northumberland Gazette before entering the field of journalism. He was editor of the Bucks County Messenger in 1821. A year later, he moved to Washington, D.C., and studied political movements while working for the printing firm of Gales and Seaton. He married Margaret Brua and returned to Harrisburg, Pennsylvania where he purchased and ran the Republican in 1824.

Cameron served as state printer of Pennsylvania from 1825 until 1827 and was state adjutant general in 1826. He constructed several rail lines and merged them into the Northern Central Railway. He founded the Bank of Middletown in 1832 and engaged in other business enterprises. In 1838, he was appointed as commissioner to settle claims of the Winnebago Indians.

He became a Whig Party member, and later became a member of the Democratic Party, before being elected to replace James Buchanan in the Senate in 1845. He switched to the Republican Party and was nominated for President, but gave his support for Lincoln at the Republican National Convention of 1860. Lincoln, as part of a political bargain, named him Secretary of War. Because of allegations of corruption, however, he was forced to resign early in 1862. He then served as US Minister to Russia.

In 1867, Cameron was again elected to the Senate and served there until 1877, when on assurances from the Pennsylvania legislature that his son, James Donald Cameron would be the successor to his seat, he resigned. His son had already been named as Secretary of War in 1876.

Cameron retired to his farm at Donegal Springs near Maytown, Pennsylvania where he died on June 26, 1889. He is buried in the Harrisburg Cemetery in Harrisburg, Pennsylvania. Cameron County, Pennsylvania, and Cameron Parish, Louisiana, are named in his honor.