The former Wolverhampton Wanderers boss was relieved of his duties on Monday morning after overseeing a 3-0 defeat to Manchester United in the Premier League at the weekend.
Santo lost three of his last four games at the helm - overseeing defeats to Vitesse and West Ham United earlier in October - and the 47-year-old has now been relieved of his duties.
Speaking to the official Tottenham Hotspur website, director of football Fabio Paratici said: "I know how much Nuno and his coaching staff wanted to succeed and I regret that we have had to take this decision.
"Nuno is a true gentleman and will always be welcome here. We would like to thank him and his coaching staff and wish them well for the future."
Santo won nine, drew one and lost seven of his 17 games in charge of Spurs and leaves with the Lilywhites sat eighth in the Premier League table. body check tags ::