He opened a studio in Boston, but as sitters were few, he made a trip through New England, taking commissions for portraits, and also visited Charleston, South Carolina, where some of his paintings may be seen today.
At Concord, New Hampshire, Morse met Miss Lucretia Walker, a beautiful and cultivated young woman, and they were married in 1818.

Morse then settled in New York.

His reputation as a painter increased steadily, though he gained little money, and in 1825 he was in Washington painting a portrait of the Marquis La Fayette, for the city of New York, when he heard from his father the bitter news of his wife's death in New Haven, then a journey of seven days from Washington.

Leaving the portrait of La Fayette unfinished, the heartbroken artist made his way home.
Two years afterwards Morse was again obsessed with the marvels of electricity, as he had been in college.

The occasion this time was a series of lectures on that subject given by James Freeman Dana before the New York Athenaeum in the chapel of Columbia College.