Before NCIS: New Orleans, CBS had commissioned a different NCIS: Los Angeles spin-off called NCIS: Red, written and produced by Shane Brennan, about a mobile team of agents traveling the country to solve crimes.

The abandoned NCIS: Red pilot had cast John Corbett as lead agent Roy, with Miguel Ferrer, Edwin Hodge, Scott Grimes, Gillian Alexy, and Kim Raver also attached, but CBS decided in May 2013 not to pick it up to series.

NCIS: New Orleans was introduced via a two-part backdoor pilot titled 'Crescent City (Part I)' and 'Part II', written by Gary Glasberg and filmed in New Orleans in February 2014, airing during NCIS season 11 before the spin-off was picked up to series in May 2014.

Series creator and showrunner Gary Glasberg produced the show's third season before dying on September 28, 2016, shortly after that season began.

Showrunner Brad Kern, who took over in January 2016, was investigated multiple times for inappropriate behavior toward women; he was replaced as showrunner by Christopher Silber in May 2018, suspended in June 2018 during a third CBS investigation, and ultimately fired by CBS in October 2018.

Zoe McLellan, who played Special Agent Meredith Brody, left the series in July 2016 'for creative reasons' and was replaced by Vanessa Ferlito as Special Agent Tammy Gregorio.

In April 2019, the plot description for the season 5 finale 'The River Styx, Part I', set in South Ossetia and referring to it as a 'war-torn Russian province', prompted Georgian President Salome Zourabichvili to publicly criticize CBS on Twitter for disrespecting Georgia's territorial integrity; CBS never responded, though the following episode's description dropped the reference to Russia.

NCIS: New Orleans was the first series in the NCIS franchise to come to an end, concluding with its seventh season finale on May 23, 2021.