Guthrie married Catherine Murray, daughter of Magnus Miller Murray, the lawyer, businessman, and two-time mayor of Pittsburgh.[3] Guthrie served in the Mexican War with the Duquesne Grays. He was appointed "Collector of Customs" for the port of Pittsburgh.
Guthrie served two terms as mayor. During his terms, Guthrie appointed a new police force who ended the lawlessness of 1851 in Pittsburgh.[3] Guthrie was the father of George W. Guthrie, who would also serve as mayor.
Guthrie was a member of the Pennsylvania Constitutional Convention of 1872–73.[3]