Howe returned to the United States and in 1831 received a proposal to organize a New England asylum for the blind at Boston. He set out at once for Europe to investigate the problem. There another revolt (Polish) diverted him. After a brief imprisonment he returned to Boston in July 1832. He began receiving a few blind children at his father's house in Pleasant Street, the beginning of what was to become the Perkins School for the Blind. Howe also interested himself in the condition and treatment of mentally defective children and lobbied strenuously for legislation providing for aid and education for the blind, the deaf, and the mentally ill.

In 1843 he married Julia Ward (Howe, Julia Ward), who later wrote the Civil War's “Battle Hymn of the Republic.” Both were ardent abolitionists and members of the Free-Soil Party.