He completed his formal education at the École polytechnique fédérale de Zurich in Zurich, Switzerland, receiving his degree in 1919, and emigrated to the USA in 1920. He worked for some time at the architectural firm of Hubbell & Benes in Cleveland, Ohio, before setting up his own practice in New York City in 1923.
In 1929, Philadelphia architect George Howe invited Lescaze to form a partnership, which was named Howe & Lescaze. Within just a few weeks after joining forces, the duo began work on a large project for downtown Philadelphia. The resulting structure, completed in 1932, was the Philadelphia Savings Fund Society (PSFS) building, which is today generally considered the first International Modernist skyscraper, and the first International Style building of wide significance in the United States. Lescaze is generally given credit for the design: contemporary letters from Howe to Lescaze quote the former insisting to the latter that "the design is definitely yours." The structure replaced the bank's former headquarters in Philadelphia, a classicist structure near Washington Square built in 1897.