Before the match, United's coach Ole Gunnar Solskjaer had the lowest odds of getting fired, but it was Tottenham's Santo who got to go.
"I know how much Nuno and his staff wanted to continue and I regret that we had to make this decision," said Tottenham club director Fabio Paratici in a statement.
"Nuno is a true gentleman and will always be welcome here," Paratici continues.
Tottenham are eight in the table after ten rounds.
The club is ten points behind London rival Chelsea who tops.