He has worked as a research scientist at Los Alamos National Laboratory and Massachusetts Institute of Technology, and in the financial services industry.

Zweig proposed the existence of quarks at CERN, independently of Murray Gell-Mann, shortly after defending his PhD dissertation.

Zweig dubbed them "aces", after the four playing cards, because he speculated there were four of them (on the basis of the four extant leptons known at the time).

In 2003, Zweig joined the quantitative hedge fund Renaissance Technologies, founded by the former Cold War code breaker James Simons.

Once his four-year confidentiality agreement with Renaissance Technologies expired, the 78-year-old Zweig returned to Wall Street and co-founded a quantitative hedge fund, called Signition, with two younger partners.