Born in Florence, South Carolina, he became a student at the National Academy of Design in New York City, working with Charles Webster Hawthorne.

After Johnson married Danish textile artist Holcha Krake, the couple lived for some time in Scandinavia.

A substantial collection of his paintings, watercolors, and prints is held by the Smithsonian American Art Museum, which has organized and circulated major exhibitions of his works.

[4]: 10–17  Johnson received a number of awards at the National Academy of Design, and applied for a coveted Pulitzer Travel Scholarship in his final year.

[8] During his time as an artist, Johnson worked in a variety of medias: woodcuts, oil, water colors, pen and ink, and serigraphy.

[4]: 41  Other winners of the fine art award include Palmer Hayden, May Howard Jackson and Laura Wheeler Waring.

[2] Although the Florence Morning News described Johnson condescendingly as a "humble ... Negro youth", it also stated that he had "real genius".

On route from Denmark the couple visited Germany, The Netherlands, Belgium and finally France, where they took the train from Paris to Marseilles to board the ferry to Tunisia.

What followed was a three-month odyssey of exploration where the couple visited the capital Tūnis, studied indigenous Berber pottery and textiles at Nabeul and Kairouan and took expeditions to Sousse, Bardo and Hammamet.

The couple both sketched on their tours, creating works that both captured the local North African people and Tunisia’s ancient architectural wonders.

Neither Johnson nor Holcha Krake had worked or shown ceramics prior to their Tunisian trip and the exhibition was given high praise.

[4]: 117 [8] After Johnson returned to the United States in 1938," over the course of the next decade, his art transformed into the intense, "primitivist" style he is recognized for today.

There he and other teachers instructed about 600 students per week, as part of a local Federal Art Project supported by the Works Progress Administration.

Harsher realities of Negro life were depicted in Chain Gang and Moon over Harlem, which was a response to the 1943 racial riots in New York.

[4]: 123–180  His pieces emphasized striking and vibrant colors and simplistic figures, and his depictions of African American culture began to draw on his upbringing in the rural South.

"Johnson's grief over his wife's tragic death in 1944, compounded by his own untreated medical issues, precipitated a mental breakdown and subsequent institutionalization.

[14][18] Instead, Helen Harriton, Mary Beattie Brady, and others arranged with the court to have Johnson's belongings delivered to the Harmon Foundation with unconditional rights over all works.

On April 19, 1967, the Harmon Foundation gave more than 1,000 paintings, watercolors, and prints by Johnson to the Smithsonian American Art Museum.

[23] Beginning with Laylah Ali in 2002, the Foundation has awarded the William H. Johnson Prize annual to an early career African American artist.

[24][25] For the 2005 U.S. Postage stamp panel titled "To Form a More Perfect Union: Seeking Equal Rights for African Americans," art director Ethel Kessler used Johnson's 1941 silk-screen print Training for War to illustrate the segregation of American soldiers that preceded President Harry S. Truman's July 26, 1948 Executive Order 9981, mandating full integration in all branches of the U.S.

Postal Service issued a stamp in Johnson's honor, recognizing him as one of the nation's foremost African-American artists and a major figure in 20th-century American art.

The stamp, the 11th in the "American Treasures" series, showcases his painting Flowers (1939–40), which depicts brightly colored blooms on a small red table.

"[28] The statue was created as a piece of commemoration to Johnson as a native artist of Florence and for his contributions through his artwork that were able to show the beauty of his city from within.