Launch from Cape Canaveral (KSC); landing on the Edwards AFB; ISS-ULF-2 MPLM Leonardo.

Following a two day solo flight Endeavour docked to the ISS on November 16, 2008. Common work with the ISS expedition 18 was performed. Sandra Magnus was transferred to the ISS and Gregory Chamitoff to the STS-126 crew for returning to the Earth.

STS-126 included the Leonardo Multi-Purpose Logistics Module (MPLM) on its fifth spaceflight. Leonardo held over 14,000 pounds of supplies and equipment. Among the items packed into the MPLM were two new crew quarters racks, a second galley (kitchen) for the Destiny laboratory, a second Waste and Hygiene Compartment (WHC) rack (lavatory), the advanced Resistive Exercise Device (aRED), two water reclamation racks, spare hardware, and new experiments. Also included in Leonardo was the General Laboratory Active Cryogenic ISS Experiment Refrigerator, or GLACIER, a double locker cryogenic freezer for transporting and preserving science experiments. The shuttle also carried irradiated turkey, candied yams, stuffing and dessert for a special Thanksgiving meal at the station, as well as an Official Flight Kit with mementos for those who supported the astronauts and helped them complete their mission successfully.

Also carried was a Lightweight MPESS Carrier (LMC) carrying a Flex Hose Rotary Coupler (FHRC) and returning a Nitrogen Assembly Tank from ‘Quest’ for refurbishment.

The first EVA by Heidemarie Stefanyshyn-Piper and Stephen Bowen occured on November 18, 2008 (6h 52m) to replace a depleted nitrogen tank and a device used to help the flow of coolant from the truss, the backbone of the station. They also removed thermal covers from the Japanese Kibo module to inspect the berthing mechanism where the module's exposed facility will be installed during the STS-127 mission in 2009. They also started inspecting, cleaning and lubricating the starboard SARJ and begin replacing 11 of 12 trundle bearings. One was replaced during the STS-124 mission in June 2008. About halfway into the spacewalk, one of the grease guns that Heidemarie Stefanyshyn-Piper was preparing to use on the SARJ released some braycote grease into her crew lock bag, which is the tool bag the spacewalkers use during their activities. As she was cleaning the inside of the bag, it drifted away from her and toward the aft and starboard portion of the International Space Station. Inside the bag were two grease guns, scrapers, several wipes and tethers and some tool caddies. Stephen Bowen then shared bag and equipment with her.

On flight day 6 there were no EVA activities and the crew installed two crew quarters racks into the Harmony node, and installed a rack with equipment to be returned to Earth into the MPLM (Leonardo). The crew also began working on activating the Water Recovery System, so that samples of water from two areas could be taken and returned to Earth with Endeavour.

The second EVA was performed by Heidemarie Stefanyshyn-Piper and Robert Kimbrough on November 20, 2008 (6h 45m) to relocate two equipment carts, setting the stage for the installation of the starboard S6 truss (scheduled for February 2009). The spacewalkers also lubricated the end effector, or hand, of the Canadarm2, the station's robotic arm. They also continued lubricating the starboard SARJ and replacing trundle bearings.

On flight day 8 Michael Fincke and Sandra Magnus tested latches on the Exposed Facility Berthing Mechanism for the Japanese Kibo laboratory. Sandra Magnus continued with the installation of the Total Organic Carbon Analyzer (TOCA), while engineers on the ground worked through troubleshooting of the Urine Processor Assembly. The component ran initially on Thursday evening, but shut itself down during that initial test, and shut down again the following morning after two hours of operations.

The third EVA by Heidemarie Stefanyshyn-Piper and Stephen Bowen was conducted on November 22, 2008 (6h 57m) to complete starboard SARJ cleaning, lubricating and trundle bearing work.

The two crews (Station and Shuttle) continued transfer operations on Flight day 10, and Michael Fincke and Donald Pettit worked together to reconfigure the Urine Processing Assembly (UPA) to try to dampen any vibration that may be contributing to the unit's shutting down prematurely. The unit had continued to operate sporadically, shutting itself down after two to three hours of operations, and the engineers on the ground were still evaluating the possible causes and solutions.

The fourth and final EVA by Stephen Bowen and Robert Kimbrough was performed on November 24, 2008 (6h 07m) to remove several thermal covers on the port SARJ. Robert Kimbrough lubricated the port SARJ, while Stephen Bowen reinstalled the thermal insulation covers (removed on first EVA) on Kibo. He then installed two GPS antennas on Kibo's logistics module, while Robert Kimbrough installed a new TV camera on the truss. Meanwhile the managers on the groud had decided to extend Endeavours mission to allow the crews more time to resolve the issues with the Urine Processing Assembly. And the UPA finally appeared to be functioning normally after the modifications performed by the crew on orbit.

Due to bad weather at the primary landing site at Cape Canaveral (KSC) the Endeavour landed with two orbits delay at the Edwards AFB.

Sandra Magnus landed on March 28, 2009 at 19:13 UTC with STS-119.