Inter are 12th in the Serie A table after a 1-0 loss at Sampdoria on Sunday, their fourth defeat in five league games.
Former Netherlands defender and ex-Ajax boss De Boer, 46, was heavily linked with vacancies at Premier League clubs Everton and Southampton in the summer.
Inter visit Southampton in the Europa League on Thursday (20:05 GMT).
Youth team coach Stefano Vecchi will take charge of the first team for that fixture.
De Boer tweeted that “to carry out this project needed more time” and thanked Inter supporters for their support.
Before joining Inter, De Boer had taken Ajax to four successive Dutch titles but lost out to PSV Eindhoven on the final day of last season.
He signed a three-year contract with Inter in August, replacing former Manchester City manager Roberto Mancini.
It is six years since Inter won the treble of Serie A, Coppa Italia and Champions League under Jose Mourinho, now Manchester United boss, but since coming second in 2011 they have finished sixth, ninth, fifth, eighth and fourth.
They are now looking for a ninth manager since Mourinho left in the summer of 2010.
Newcastle boss Rafael Benitez, Leicester manager Claudio Ranieri and Watford boss Walter Mazzarri have all coached at the San Siro in the past six years.
Analysis: ‘They haven’t been the Inter of old’
Former Inter Milan midfielder Paul Ince on BBC World Service
I feel sorry for Frank. He’s a top manager. He didn’t get much time.
Sometimes when you’re at a big club, you don’t really get the time. The results haven’t been great. One of the major things that hasn’t helped him is AC Milan have done well under Vincenzo Montella.
Inter of the last three or four years haven’t been the Inter of old. They don’t attract the best players like Juve, Roma and Napoli. I feel since [former owner] Massimo Moratti sold his major stake, they haven’t been the same.
They’ve gone through so many managers in the past six or seven years. When I was there in 1995-96, it was full of Italian players who cared about the club and fans. I watched their game the other day and they only had about three Italian players.