The 56-year-old is embarking on a second spell with the Mariners having spent two years in charge of the club between 2004 and 2006.
In that time, Slade guided the team to the League Two playoff final, but they were beaten by a single goal against Cheltenham Town.
The Wokingham-born coach has now returned as successor to Marcus Bignot, who was sacked on Monday after just five months in charge.
Grimsby confirmed on their official website that Slade will "take over first team affairs with immediate effect" and that Paul Wilkinson will be his assistant coach.
The Mariners are currently 14th in League Two.