Launch from Cape Canaveral (KSC); landing 2000 km south of Hawaii in the Pacific Ocean. CSM was named "Casper" and the LM "Orion".

The launch of Apollo 16 was delayed one month from March 17, 1972 to April 16, 1972. This was the first launch delay in the Apollo program due to a technical problem. During the delay, the spacesuits, a spacecraft separation mechanism and batteries in the Lunar Module (LM) were modified and tested. There were concerns that the explosive mechanism designed to separate the docking ring from the Command Module would not create enough pressure to completely sever the ring. This, along with a dexterity issue in John Young's spacesuit and fluctuations in the capacity of the Lunar Module batteries, required investigation and trouble-shooting. In January 1972, three months before the planned April launch date, a fuel tank in the Command Module was accidentally damaged during a routine test. The rocket was returned to the Vehicle Assembly Building, the fuel tank replaced and the rocket returned to the launch pad in February in time for the scheduled launch

John Young, Thomas Mattingly and Charles Duke continued preparing for Lunar Module activation and undocking shortly after waking up to begin flight day five. The boom that extended the mass spectrometer out from the Command/Service Module's Scientific Instruments Bay was stuck in a semi-deployed position. It was decided that John Young and Charles Duke would visually inspect the boom after undocking from the CSM in the LM. John Young and Charles Duke entered the LM for activation and checkout of the spacecraft's systems. Despite entering the LM forty minutes ahead of schedule, John Young and Charles Duke completed preparations only ten minutes early due to numerous delays in the process. With the preparations finished, John Young and Charles Duke undocked in the LM Orion from Thomas Mattingly in the Command/Service Module Casper 96 hours, 13 minutes, 13 seconds into the mission. For the rest of the two spacecrafts' pass over the near side of the Moon, Thomas Mattingly prepared to shift Casper to a circular orbit while John Young and Duke prepared Orion for the descent to the lunar surface. At this point, during tests of the CSM's steerable rocket engine in preparation for the burn to modify the craft's orbit, a malfunction occurred in the engine's backup system. According to mission rules, Orion would have then re-docked with Casper, in case mission control decided to abort the landing and use the Lunar Module's engines for the return trip to Earth. After several hours of analysis, however, mission controllers determined that the malfunction could be worked around and John Young and Charles Duke could proceed with the landing. As a result of this, powered descent to the lunar surface began about six hours behind schedule. Because of the delay, John Young and Charles Duke began their descent to the surface at an altitude higher than that of any previous mission, at 20.1 kilometres (10.9 nmi). At an altitude of about 4,000 m (13,000 ft), John Young was able to view the landing site in its entirety. Throttle-down of the LM's landing engine occurred on time and the spacecraft tilted forward to its landing orientation at an altitude of 2,200 m (7,200 ft). The Lunar Module Orion, with John Young and Charles Duke inside, landed 270 m (890 ft) north and 60 m (200 ft) west of the planned landing site at 104 hours, 29 minutes, and 35 seconds into the mission, at 2:23:35 UTC on April 21, 1972

Apollo 15 marked the fifth manned moonlanding. As landing site scientists choose the Descartes Highlands. The lunar surface stay-time was 71h 2m. A LRV was used for the second time.

Three EVAs were performed by John Young and Charles Duke. The first EVA was performed on April 21, 1972 (7h 11m). The astronauts activated the first experiments and drove with the LRV to the Spook Crater. They also collected samples. The second EVA was performed on April 22, 1972 (7h 23m). 11.1 km with the LRV had been driven, samples were collected from near the Stubby and Wreck Craters. The third and final EVA was on April 23, 1972 (5h 40m) which brought the crew to the North Ray Crater. All in all 95,71 kg of lunar samples were collected.

Thomas Mattingly performed a trans Earth EVA on April 25, 1972 of 1h 24m during returning to Earth to retrieve the film cassettes from the scientific instrument module cameras, inspect the equipment, and expose a microbial response experiment to the space environment. On the return flight several scientific experiments were performed.

The crew splashed down 5 km far from the recovery ship USS Ticonderoga.