The series originally appeared on ABC's development slate in late 2010 under the working title 'Man Up', then was renamed 'Last Days of Man' when the pilot was greenlit in January 2011, before finally becoming 'Last Man Standing'.

Nick Jonas guest-starred as Ryan Vogelson in a single season 1 episode before the role was recast and expanded, with Jordan Masterson taking over the part as a recurring and later main character from season 2 onward.

Alexandra Krosney, who originated the role of Kristin in season 1, was let go from the show for creative reasons in June 2012 and replaced by Amanda Fuller for season 2.

Twin actors Luke and Evan Kruntchev, who played Boyd in season 1, did not return for season 2; the character was replaced by Flynn Morrison and aged up from two to five years old.

When the show moved to Fox for season 7, Molly Ephraim (Mandy) and Flynn Morrison (Boyd) chose not to return and were recast with Molly McCook and Jet Jurgensmeyer, while Kaitlyn Dever stepped back to a recurring role as Eve due to her commitment to the Netflix miniseries Unbelievable.

The show had three different showrunners during its first season and a half: creator Jack Burditt ran the first thirteen episodes, followed by Kevin Abbott, who briefly left for a rehab stint before returning full-time, and then Tim Doyle took over in June 2012.

After ABC's cancellation and the show's subsequent revival on Fox in 2018, the entire physical set had to be rebuilt from scratch at Radford Studio Center.

Production on the series was shut down in March 2020 due to the COVID-19 pandemic.

ABC's cancellation of the series in May 2017 sparked significant fan backlash, including a Change.org petition that surpassed 380,000 signatures within weeks and grew to 438,000 a year later.

The cancellation came shortly after star Tim Allen, a real-life Republican, made controversial comments on Jimmy Kimmel Live! comparing being a Republican in Hollywood to '1930s Germany,' remarks that drew widespread criticism.

Tim Allen and Hector Elizondo appeared in character as Mike Baxter and Ed Alzate in a crossover episode with the fellow ABC Friday sitcom Cristela in 2014.