Ordained after graduating from Harvard Divinity School (1847), Higginson became pastor of the First Religious Society of Newburyport, Massachusetts, where he preached a social gospel too liberal even for Unitarians. Two years later his progressive views on temperance, women's rights, labour, and slavery caused him to lose his congregation.

On the passage of the Fugitive Slave Act (Fugitive Slave Acts) (1850), Higginson joined the Boston Vigilance Committee to aid escaping slaves. While pastor of a “Free Church” in Worcester, Massachusetts (1852–61), he took a leading part in liberating the fugitive Anthony Burns (1854), and he supported John Brown (Brown, John) both in Kansas (1856) and in his raid on Harpers Ferry, Virginia (1859). During the Civil War Higginson accepted command of the 1st South Carolina Volunteers, later the 33rd U.S. Colored Troops, the first black regiment in the U.S. armed forces. After 1864 he wrote a series of popular biographies and histories and a novel. Higginson discovered and encouraged the poet Emily Dickinson (Dickinson, Emily).