In applied mathematics, he worked with aerodynamics, elasticity, optimization, and differential games, which he is most known for.
His first post after the war ended was at Notre Dame, but he left in 1947 due to salary issues.
While at RAND, he worked with researchers including Richard E. Bellman, Leonard D. Berkovitz, David H. Blackwell, John M. Danskin, Melvin Dresher, Wendell H. Fleming, Irving L. Glicksberg, Oliver A.
His work has significant influence on mathematical optimization including fundamental concepts such as dynamic programming (Richard E. Bellman) and the Pontryagin maximum principle (Breitner 2005) which are widely used in economics and many other fields.
Isaacs was a professor of Mathematical Sciences and Electrical Engineering at the Johns Hopkins University between 1967 and his retirement in 1977.