The 52-year-old joins the club four days after the departure of Leonid Slutsky following a run of just four wins from the Tigers' 20 Championship games this season.
During his time as Saints boss, Adkins led the side to back-to-back promotions from League One to the Premier League before being replaced by Mauricio Pochettino in January 2013.
At Scunthorpe United, Adkins earned two promotions from League One and most recently was in charge of Sheffield United, but was sacked by the club in May 2016.
Adkins, who has been joined by long-term assistant Andy Crosby, will coach his new side for the first time today and will be in the dugout at the KCOM this Saturday for the visit of Brentford.
Hull are currently 20th in the Championship, three points above the dropzone and without a league win since mid-October.