MacGyver takes place in the same fictional universe as two other Peter M. Lenkov reboots, Hawaii Five-0 and Magnum P.I., with the three shows collectively nicknamed the 'Lenkov-verse'.

The assassin character Murdoc, introduced as 'Suspect 218', is a nod to the original 1985 series, and in a guest appearance Michael Des Barres, who played Murdoc in the original MacGyver series, appeared as Murdoc's mentor Nicholas Helman.

Bruce McGill, who played Jack Dalton in the original 1985 MacGyver series, later guest-starred in the reboot as LAPD Detective Greer.

The original pilot, written by Paul Downs Colaizzo and directed by James Wan, was scrapped by CBS in June 2016, and an entirely new pilot was ordered and directed by David Von Ancken after Wan had to step back due to scheduling conflicts.

The first pilot version featured a different cast, including Joshua Boone, Addison Timlin and Michelle Krusiec, but when CBS ordered a new pilot only Lucas Till and George Eads were retained from the original casting.

Creator Peter Lenkov and director James Wan stated in 2016 that they wanted to cast Richard Dean Anderson, the star of the original MacGyver, in the new series, saying they were 'MacGyver fanatics' hoping to get him involved.

Showrunner Peter M. Lenkov was fired in July 2020 after an investigation into allegations he created a hostile work environment; star Lucas Till later told Vanity Fair he had been verbally abused and body-shamed by Lenkov and felt suicidal during the first year of the show because of it.

George Eads left the series midway through season 3 after asking to be released from his contract in order to spend more time with his young daughter in Los Angeles, since the show filmed in Atlanta; his character Jack Dalton was later killed off-screen in season 5.