The commercial satellites were deployed successfully and subsequently propelled into their operational geosynchronous orbits by McDonnell Douglas PAM-D kickmotors. The two satellites were SBS 3, owned by Satellite Business Systems, and Anik C3, owned by Telesat Canada; both were Hughes-built HS-376-series satellites. In addition, STS-5 carried a West German-sponsored microgravity GAS experiment canister in the payload bay. The crew also conducted three student-designed experiments during the flight.

Lenoir and Allen were to perform a spacewalk, the first of the Shuttle program, to test newly developed space suits. The space suits were developed as cheaper and less complicated alternatives to the Apollo versions. The test was delayed by one day due to Lenoir succumbing to motion sickness. Then a poorly functioning oxygen regulator in Lenoir's suit and a broken recirculation fan in Allen's caused them to cancel the extravehicular activity (EVA) entirely. It was the first time in the history of the space program that an EVA had been cancelled due to space suit issues.

Columbia landed on Runway 22 at Edwards Air Force Base on 16 November 1982, at 6:33 am PST, having traveled 2 million miles in 81 orbits during a mission that lasted 5 days, 2 hours, 14 minutes and 26 seconds. Columbia was returned to KSC on 22 November 1982. STS-5 was the first shuttle flight in which the crew did not wear pressure suits for the launch, reentry, and landing portions of the flight, similar to the Soviet Voskhod and Soyuz missions prior to the ill-fated Soyuz 11 mission in 1971.