Former Argentina striker Crespo, who represented Chelsea, Inter Milan and AC Milan among other European clubs as a player, replaced compatriot Luis Zubeldia who parted ways with Sao Paulo after winning only two of their first 12 league games.
"(Crespo) is a great professional who already knows the club, has won a title here and the time has come for him to return. We're delighted to have him back," club president Julio Casares said in a statement.
The 49-year-old's first spell as Sao Paulo coach ended in October 2021, less than five months after winning the league, following a disappointing start to their title defence.
Crespo led Emirati club Al Ain to the Asian Champions League Elite title in May last year, earning them a place at the ongoing Club World Cup. He was sacked in November following a poor run of results.