St. Francis was born in 1182 to a wealthy family. As a soldier, he had a mystical experience and decided to care for the sick. In 1206 he had a vision in which Christ called him to repair His church. He founded three orders: Franciscans, Poor Clares and the Order of Penance, a lay order. He died in 1226, at age 44. He is the patron saint of ecologists. The murals by Thomas S. La Farge, the nephew of Cathedral designer C. Grant LaFarge, depict scenes from the life of St. Francis. Over the altar is St. Francis and St. Clare with the crucified Christ.

At the entrance is the burial chamber for the resident archbishops of Washington. Patrick Cardinal O'Boyle, Washington's second archbishop and first resident archbishop, is buried here.