Challenger lifted off from Kennedy Space Center at 8 am EST on February 3, 1984. It was estimated that 100,000 people attended the launch. Two communications satellites were deployed about 8 hours after launch; one, Westar 6, was for America's Western Union, and the other, Palapa B2, for Indonesia. However, the Payload Assist Modules (PAM) for both satellites malfunctioned, placing them into a lower-than-planned orbit. Both satellites were retrieved successfully in November 1984 during STS-51-A, which was conducted by the orbiter Discovery.

The STS-41-B crew included commander Vance D. Brand, making his second Shuttle flight; pilot Robert L. Gibson; and mission specialists Bruce McCandless II, Ronald E. McNair, and Robert L. Stewart.

On the fourth day of the mission, astronauts McCandless and Stewart performed the first untethered spacewalk, operating the Manned Maneuvering Unit (MMU) for the first time. McCandless ventured out 320 feet (98 m) from the orbiter, while Stewart tested the "work station" foot restraint at the end of the Remote Manipulator System. On the seventh day of the mission, both astronauts performed another EVA to practice capture procedures for the Solar Maximum Mission satellite retrieval and repair operation, which was planned for the next mission, STS-41-C.

STS-41-B also achieved the reflight of the West German-sponsored SPAS-1 pallet/satellite, which had originally flown on STS-7. This time, however, it remained in the payload bay due to an electrical problem in the RMS. The mission also carried five GAS canisters, six live rats in the middeck area, a Cinema-360 camera and a continuation of the Continuous Flow Electrophoresis System and Monodisperse Latex Reactor experiments.[8] Included in one of the GAS canisters was the first experiment by a high school team to fly in space. The experiment, on seed germination and growth in zero gravity, was created and built by a team from Brighton High School in Utah through a partnership with Utah State University.

The 7-day, 23-hour, 15-minute, 55-second flight ended on February 11, 1984 with a successful landing at Kennedy Space Center's Shuttle Landing Facility. This marked the first landing of a spacecraft at its launch site. Challenger completed 127 orbits and traveled 2.8 million miles.