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Change UK has lost six of its 11 MPs following a disappointing performance in last month's EU elections, when it failed to get a single MEP elected.
The party announced that a new party leader, Anna Soubry, had been elected.
She said she was "deeply disappointed" that Heidi Allen, Chuka Umunna, Sarah Wollaston, Angela Smith, Luciana Berger and Gavin Shuker had left.
The departing MPs said they would be "returning to supporting each other as an independent grouping of MPs".
Change UK - formally known as the Independent Group - was formed earlier this year by MPs who quit Labour and the Conservatives.
A joint statement from the six outgoing members said they believed it was their priority now "to provide collegiate leadership to bring people together in the national interest".
"We know the landscape will continue to shift within the political environment and have concluded that by returning to sit as independents, we will be best placed to work cross-party and respond flexibly.
"We wish our colleagues well as they continue to build Change UK."
Ms Soubry, who has taken over from Ms Allen as leader, said: "I'm deeply disappointed that at such a crucial time in British politics our former colleagues have made this decision.
"Now is not the time to walk away, but instead to roll up our sleeves and stand up for the sensible mainstream centre ground which is unrepresented in British politics today."
She said the party was "as determined to fix Britain's broken politics as we were when we left our former parties".
BBC political correspondent Ben Wright said there had "clearly been turmoil in the party's ranks for number of weeks".
"It has been obvious that there was an internal disagreement over where the party should be positioning itself, what its long term tactics should be, whether it should be cosying up to the Lib Dems or maintaining itself as an independent party," he said.
"Change UK was being squeezed by the other parties campaigning for Remain and didn't keep the momentum going that it had earlier in the year when it launched."
The party had pledged to push for any Brexit deal negotiated by the government to be voted on at a referendum - or "People's Vote" - in which it would campaign for the UK to remain in the EU.
But in last month's European Parliament elections, Change UK gained only 3.4% of the vote.