Launch from Cape Canaveral (KSC); landing on Cape Canaveral (KSC). The launch was originally scheduled for October 31, 1996, but was bumped back to November 19, 1996 for several reasons.

STS-80 carried out the mission ORFEUS-SPAS-02. The main component of the satellite, the ORFEUS telescope, had two spectrographs, for far and extreme ultraviolet. Another spectrograph, the Interstellar Medium Absorption Profile Spectrograph, was also on board the satellite.

Two planned EVA's by Thomas Jones and Tamara Jernigan were cancelled, because the airlock hatch couldn't be opened.

Deploying and retrieval of German built astronomy satellite ORFEUS-SPAS-02 and of the Wake Shield Facility (WSF 03) were done by the crew. This satellite created an ultra-vacuum behind it, allowing for the creation of semiconductor thin films for use in advanced electronics. WSF created seven films before being recaptured by Columbia's robotic arm after three days of flight.

Another inclusion was a Space Experiment Module (SEM). The SEM included student research projects selected to fly into space. This was the first flight of the program. Among the experiments conducted were analysis of bacteria growth on food in orbit, crystal growth in space, and microgravity's effect on a pendulum.

NIH.R4 was an experiment conducted for the National Institute of Health and Oregon Health Sciences University. It was designed to test the effects of spaceflight on circulation and vascular constriction. Biological Research in Canister (BRIC) explored gravity's effects on tobacco and tomato seedlings. Visualization in an Experimental Water Capillary Pumped Loop (VIEW-CPL) was conducted to test a new idea in thermal spacecraft management. The Commercial MDA ITA Experiment were a variety of experiments submitted by high school and middle school students sponsored by Information Technology Associates.

Several secondary experiments were carried out by the Columbia.

It was the longest Shuttle mission to date. The landing was postponed two days due of bad weather at the landing site. Story Musgrave set a new record for being the oldest man in space. This record have since been surpassed.