"Karpin has been appointed Spartak's caretaker coach until the end of the year," the club's spokesman Alexei Matveyev told Reuters.
Karpin, 43, replaces Spaniard Unai Emery, who was sacked following a 5-1 home thrashing by city rivals Dynamo in a Russian Premier League derby on Sunday.
He faces a stern test in his first game back on Friday when his team host champions Zenit St Petersburg.
Karpin had a distinguished playing career with Spartak and Spanish clubs Valencia, Real Sociedad and Celta Vigo but had no coaching experience before becoming general director at the Moscow club in August 2008. Eight months later he fired Denmark's Michael Laudrup as coach and took over the hot seat.
Karpin combined the two jobs for three years before resigning in favour of ex-Valencia boss Emery in May despite Spartak finishing last season in second place and qualifying for the Champions League.
In April 2011, he quit the coaching role after a series of poor results left the team bottom of the table before changing his mind a few days later.
Spartak, Russia's most successful and popular club with nine league titles between 1992 and 2001, have not claimed any domestic trophies since winning the Russian Cup in 2003.
Sunday's defeat left them in seventh place, 10 points behind leaders CSKA Moscow, who play Zenit later on Monday.
Spartak have also failed to impress in Europe and have been consigned to finishing bottom of Champions League Group G with a game to spare.
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