Magoffin's administration was dominated by the secession crisis and the Civil War. Prosouthern in his sentiments, he accepted slavery and the right of a state to secede, but he believed that if the slave states presented collective demands the North would have to accept them. In a circular letter of 9 December 1860 to the slave state governors, he suggested calling a conference that would insist on strict enforcement of the Fugitive Slave Act, a division of the territories between slave and free at the thirty-seventh parallel, and a constitutional provision that would allow the South to protect its interests, perhaps by requiring a two-thirds Senate majority to pass legislation pertaining to slavery. If this proposal failed, Magoffin believed that Kentucky would join the other slave states in leaving the Union.
In response to a secessionist appeal from the Alabama governor, Magoffin replied on 28 December 1860 that "the mode and manner of defense and redress should be determined in a full and free conference of all the Southern States, and that their mutual safety requires full co-operation in carrying out the measures there agreed upon." This cooperative movement was to be completed before Abraham Lincoln's inauguration in March 1861.