The primary payload, the Compton Gamma Ray Observatory (CGRO), was deployed on flight day 3. CGRO's high-gain antenna failed to deploy on command; it was finally freed and manually deployed by Ross and Apt during an unscheduled contingency space walk, the first since April 1985. The following day, the two astronauts performed the first scheduled space walk since November 1985 to test means for astronauts to move themselves and equipment about while maintaining the then-planned Space Station Freedom. CGRO science instruments were Burst and Transient Source Experiment (BATSE), Imaging Compton Telescope (COMPTEL), Energetic Gamma Ray Experiment Telescope (EGRET) and Oriented Scintillation Spectrometer Experiment (OSSE). CGRO was the second of NASA's four Great Observatories. The Hubble Space Telescope, deployed during Mission STS-31 in April 1990, was the first. CGRO was launched on a two-year mission to search for the high-energy celestial gamma ray emissions, which cannot penetrate Earth's atmosphere. At about 35,000 pounds, CGRO was the heaviest satellite to be deployed into low-Earth orbit from the Shuttle. It was also designed to be the first satellite that could be refueled in orbit by Shuttle crews. Five months after deployment, NASA renamed the satellite the Arthur Holly Compton Gamma Ray Observatory, or Compton Observatory, after the Nobel Prize-winning physicist who did important work in gamma ray astronomy.

Secondary payloads included Crew and Equipment Translation Aids (CETA), which involved scheduled six-hour space walk by astronauts Ross and Apt (see above); Ascent Particle Monitor (APM); Shuttle Amateur Radio Experiment II (SAREX II); Protein Crystal Growth (PCG); Bioserve/Instrumentation Technology Associates Materials Dispersion Apparatus (BIMDA); Radiation Monitoring Equipment III (RME Ill); and Air Force Maui Optical Site (AMOS) experiment. Among the other payloads flown was the first flight of the Bioserve/Instrumentation Technology Associates Materials Dispersion Apparatus (BIMDA) to explore the commercial potential of experiments in the biomedical, manufacturing processes and fluid sciences fields, and the Protein Crystal Growth experiment, which has flown eight times before in various forms. Astronaut Pilot Kenneth Cameron was the primary operator of the Shuttle Amateur Radio Experiment (SAREX), although all five crew members participated as amateur radio operators. It was arguably the first time that the astronauts received fast scan amateur television video from the ham radio club station (W5RRR) at JSC.