On April 21, 1840, Magoffin married Anna Nelson Shelby, granddaughter of Kentucky's first and fifth governor, Isaac Shelby. The couple eventually had eleven children, one of whom died as an infant. Magoffin also began his political career in 1840, being appointed police judge of Harrodsburg by Governor Robert P. Letcher.
Magoffin was a delegate to the Democratic National Convention in 1848, 1856, and 1860. He served as a state senator in 1850, but refused a nomination to the U.S. House of Representatives in 1851. In 1855 was the Democratic nominee for lieutenant governor, running on a ticket with Beverly L. Clarke, who was defeated by Know Nothing candidate Charles S. Morehead.
Immediately recognizing the mounting tensions between the Northern and Southern states, Magoffin presented a plan for saving the Union to the governors of the slave-holding states on December 9, 1860. This plan was rejected, whereupon he became an ardent supporter of the Crittenden Compromise authored by Kentucky's John J. Crittenden.
Magoffin was sympathetic to the Confederacy, but believed that the people of the Commonwealth should decide what to do with regard to secession. To that end, he called the General Assembly into special session on January 17, 1861 and asked them to call for a sovereignty convention. Fearing that the majority of the Commonwealth's citizens might favor secession, the Unionist General Assembly refused to call the convention.
On April 15, 1861, Magoffin refused President Lincoln's call for troops from Kentucky, responding in a telegram: "President Lincoln, Washington, D.C. I will send not a man nor a dollar for the wicked purpose of subduing my sister Southern states. B. Magoffin" The next week, Magoffin similarly rejected a call for troops from Confederate president Jefferson Davis. Magoffin again called the General Assembly into session in May. While they still refused to call a sovereignty convention, they did pass a declaration of neutrality, which Magoffin proclaimed on May 20, 1861.
The Commonwealth's sympathies became clear, however, in a special congressional election held on June 20, 1861. Nine of Kentucky's ten congressional seats were won by Unionist candidates, with the Jackson Purchase region being the only exception. Magoffin was dealt a further blow in the August 5 elections for state legislators when supporters of the Union gained a two-thirds majority in both houses of the General Assembly as many Confederate sympathizers and State's Right's advocates boycotted the election. From that time forward, the legislature consistently overrode Magoffin's vetoes.
Following the violation of Kentucky's neutrality, first by Confederate general Leonidas Polk and then by Union general Ulysses S. Grant, the Unionist General Assembly passed a resolution calling on Magoffin to order only Confederate troops out of Kentucky. After the legislature overrode his veto, Magoffin issued the proclamation. Despite his support of the Southern cause, Magoffin denounced the November 1861 secessionist Russellville Convention, calling it a "self-constituted" conference that did not represent the will of the majority of the Commonwealth's citizens.
On August 16, 1862, Magoffin agreed to resign as governor if allowed to pick his successor. (Lieutenant Governor Linn Boyd had died in office in 1859, and Magoffin did not want Senate Speaker John F. Fisk, next in line for the governorship, to succeed him.) Under terms of the agreement, Fisk resigned as Speaker, and James F. Robinson, Magoffin's chosen successor, was elevated to that post. Two days later, Magoffin resigned, and Fisk was re-elected Speaker when Robinson assumed the governorship.
Upon his resignation, Magoffin returned to his legal practice in Harrodsburg and became wealthy investing in real estate in Chicago, Illinois. Following the war, he urged the citizens of the Commonwealth to accept the result and ratify the Thirteenth Amendment. (His plea went unheeded, as the state rejected the amendment on February 24, 1865. It was not ratified in Kentucky until March 18, 1976.) He remained interested in politics, though the only political office he held following his term as governor was in the Kentucky House of Representatives, representing Mercer County, Kentucky from 1867 to 1869.
He died in Harrodsburg and was buried in the town's Spring Hill Cemetery. Magoffin County, Kentucky, created in 1860, was named for Governor Magoffin.