Wilder replaces Neil Warnock, who parted company with Middlesbrough on Saturday following a 1-1 draw at West Bromwich Albion.
Wilder had been out of work since leaving Sheffield United back in March, with the club bottom of the Premier League table.
Wilder had been in charge of the Blades since May 2016 when they were in League One and took them to the championship in his first full season in charge.
Two seasons later Sheffield United gained promotion to the Premier League and finished in a respectable ninth position but their second season in the top flight ended in relegation.
A club statement read: “Chris brings a wealth of experience to the club, having managed over 1,000 games since taking his first steps in management with non-league Alfreton Town in 2001.
“He is a four-time promotion winner, having guided Oxford out of the Conference in 2010, won League Two with Northampton in 2016 and most recently guiding Sheffield United from the third tier to the Premier League in 2019.
“Chris was named LMA Manager of the Year after leading the Blades to the top-flight and they finished ninth on their first season back in the Premier League.
“As a player he clocked up almost 500 appearances, a century coming for Sheffield United, his hometown club. The defender also racked up three figures for Rotherham United and enjoyed successful spells with Notts County, Bradford City, and Halifax Town.”
Middlesbrough are 14th on the Championship table.
