Domenicali has been in the position of team principal since 2008 but has resigned after taking responsibility for a largely disappointing start to the F1 calendar
The popular Italian has been replaced by Marco Mattiacci, the head of Maranello's North American car operation.
He is the second leading figure in the sport to split from his team in three months. Martin Whitmarsh was ousted at McLaren at the end of January after the team's disastrous 2013 season.
Domenicali, who had been at the helm at Maranello since 2008 and worked for the company for 23 years, publicly shouldered the blame for the legendary team's lack of form.
The cars built for the new eco era - dominated by Mercedes - are so uncompetitive they were reduced to battling for points on the fringes of the top 10 at the last round in Bahrain.
Even though lead driver Fernando Alonso has finished fourth in the two previous rounds, he publicly complained on the team radio his Ferrari was uncompetitive and lacked power.
As the F1 paddock prepared to leave for the fourth round in China on Sunday, Domenicali said: “There are special moments that come along in everyone’s professional life when one needs courage to take difficult and very agonising decisions.
“It is time for a significant change. As the boss, I take responsibility, as I have always done, for our current situation.
"This decision has been taken with the aim of doing something to shake things up and for the good of this group of people that I feel very close to.
"With all my heart, I thank all the men and women in the team, the drivers and the partners for the wonderful relationship we have enjoyed over all these years. I hope that very soon, Ferrari will be back where it deserves to be.
"My final words of thanks go to our president, for having always supported me and to all our fans.
"I only regret that we have been unable to harvest what we worked so hard to sow in recent years.”
Domenicali took over after the glory years under Jean Todt and led the flame red machines to the constructors championship in his first year in charge.
And Felipe Massa only narrowly missed out on the drivers championship at the final round. Twice since then Alonso has lost out on the drivers title to Sebastian Vettel in a final round shoot out.
Ferrari started this season with high hopes that the new eco era would mark a turn in their fortunes.
But it has quickly become apparent they are consigned to another season of mediocrity behind Mercedes.
The latest moves come after Ferrari President Luca di Montezemolo attended high level talks in Bahrain over the state of the sport and its unpopular muted engines.
After watching his two drivers struggle dramatically in mid-field he left before the end of the race.
“I thank Stefano Domenicali, not only for his constant dedication and effort, but also for the great sense of responsibility he has shown, even today, in always putting the interests of Ferrari above all else," he said.
"I hold Domenicali in esteem and I have watched him grow professionally over the twenty three years we have worked together, I now wish him every success for the future.
"I also want to wish all the best to Marco Mattiacci, whom I know to be a highly regarded manager and who knows the company well. He has accepted this challenge with enthusiasm.”