Four hundred years in the future, Earth is part of the advanced and mostly-peaceful Planetary Union. The U.S.S. Orville is a mid-level exploratory vessel that is one of the planet's fleet of 3000 faster-than-light spaceships.

The ship's human and alien crew are led by rookie officer Ed Mercer, who is determined to prove his worth despite his First Officer being his ex-wife. Together, they face the wonders and dangers of outer space, while also dealing with the familiar workplace problems.