The Italian was put in charge just under a month ago, after the departure of Antonio Conte, overseeing four Premier League matches and losing the last two against AFC Bournemouth and Newcastle, leaving Spurs six points outside the top four.
In a statement on Spurs' website, chairman Daniel Levy said: "Sunday’s performance against Newcastle was wholly unacceptable.
"It was devastating to see. We can look at many reasons why it happened and whilst myself, the board, the coaches and players must all take collective responsibility, ultimately the responsibility is mine.
"Cristian will leave his current role along with his coaching staff. Cristian stepped in at a difficult point in our season and I want to thank him for the professional manner in which he and his coaching staff have conducted themselves during such a challenging time. We wish him and his staff well."
This is the second time Mason has been appointed interim boss at Spurs. He took charge when Jose Mourinho was sacked in April 2021, becoming the Premier League's youngest-ever manager at 29 years old.
A former Spurs midfielder, Mason took charge of six top-flight matches at the end of 2021/22 and won four of them. He has now been given another six matches in charge.
"Ryan knows the club and the players well," added Levy. "We shall update further on his coaching staff in due course.
"I met with the Player Committee today - the squad is determined to pull together to ensure the strongest possible finish to the season.
"We are all clear we need to deliver performances which earn your amazing support."