The 37-year-old retired from professional football this week to accept an offer to guide the Rossoneri.
Milan dismissed coach Massimiliano Allegri after last weekend's 4-3 defeat at Sassuolo left them 30 points adrift of Serie A leaders Juventus.
"I'm very happy to have come back," said Seedorf, who played 10 years at AC Milan. "It feels as though I never left the club.
"I'm very excited about this new adventure."
Seedorf, who signed a contract with the Rossoneri until June 2016, added: "I feel a sense of responsibility.
"When I left in 2012 a cycle had ended and now I have to open a new one.
"We have a lot of work to do in order to bring Milan back into the top positions of the standings."
Milan have won five of their 19 league games and are in 11th position at the halfway stage of the campaign.
Juventus go into Saturday's match against Sampdoria holding an eight-point lead over Roma and riding a 11-match winning streak in Serie A.
Juve have scored 30 goals and conceded just two in that run.
Meanwhile, Roma take on strugglers Livorno at the Stadio Olimpico on Saturday looking to keep up the pace with Juve.
The Giallorossi romped to a 4-0 triumph over Genoa last weekend to bounce back from their first loss in Serie A - a 3-0 reverse at Juve.
Livorno parted company with coach Davide Nicola and appointed Attilio Perotti as his replacement this week.
Napoli are third and hold the last Champions League qualifying spot heading into this weekend match.
The Azzurri have won their last two league games and are just two points adrift of Roma.
Elsewhere, Fiorentina coach Vincenzo Montella is set to hand news signing Alessandro Matri a start at rock-bottom Catania this weekend.
The Italian striker joined the Viola this week on a six-month loan deal from Milan.
Catania, meanwhile, have recalled Rolando Maran after parting company with Luigi De Canio following Wednesday's 4-1 loss to Serie B Siena in the Coppa Italia.
Inter Milan are fifth in the standings and have won just one of their last seven league games.
The Nerazzurri square off against Genoa at the Luigi Ferraris stadium desperate to clinch their first win in 2014.
Eighth-place Parma travel to Verona to face Chievo on the back of a 2-1 midweek loss at Lazio in the Coppa Italia.
The outcome in Rome was Parma's first loss in 2014.
Lazio and Cagliari take on Udinese and Atalanta, respectively, with both teams looking for their first win on the road this season.
Sassuolo hope to build on their famous triumph over AC Milan when they host Torino on Sunday.
Domenico Berardi struck four goals to see the Serie A newcomers stun the Italian giants 4-3 last Sunday.
The outcome halted a four-match losing streak and was Sassuolo's fourth win of the campaign.