The 2021–22 EPCR Challenge Cup was the eighth edition of the EPCR Challenge Cup, an annual second-tier rugby union competition for professional clubs. Including the predecessor competition, the original European Challenge Cup, this was the 26th edition of European club rugby's second-tier competition.

Lyon Olympique Universitaire Rugby or LOU is a French professional rugby union team based in Lyon that currently competes in the Top 14, the highest level of the country's professional league system, having been most recently promoted for the 2016–17 season after winning the 2015–16 title of the second-level Pro D2. The club has bounced between the top two levels in recent years, having also been promoted in 2011 and 2014 and relegated in 2012 and 2015.