Hennessy joined Stanford University's faculty in 1977 as an assistant professor of electrical engineering. In 1981, he drew together researchers to focus on a computer architecture known as RISC (Reduced Instruction Set Computing), a technology that would revolutionize the computer industry by increasing performance while reducing cost. During his sabbatical year in 1984, he co-founded MIPS Computer Systems to produce commercial RISC microprocessors. It was a risky concept at the time, but RISC technology now appears in devices as varied as supercomputers and smartphones.
Hennessy, who has lectured and published widely, is the co-author (with David Patterson) of two well known textbooks on computer architecture and design.
In October 2000, he was inaugurated as Stanford University's 10th president. Hennessy is a member of the National Academy of Engineering and the National Academy of Sciences, and a fellow of the American Academy of Arts and Sciences, the ACM, and the IEEE.