Christian Wakeford, who represents the Bury South constituency in northern England, said Johnson's policies were doing nothing to help the people he represents and that he was joining the main opposition Labour Party.
Wakeford was one of several lawmakers elected for the first time in 2019 who has expressed concerns over Johnson.
The prime minister has faced growing calls to quit for a series of missteps, including attending a gathering in the garden of his Downing Street office and residence in May 2020, when strict COVID-19 rules forbade almost all socialising.
Johnson has apologised, but for some lawmakers in the party, the damage has already been done, leading some to write letters of no confidence in him.
"My decision is about much more than your leadership and the disgraceful way you have conducted yourself in recent weeks," Wakeford said.
"I can no longer support a government that has shown itself consistently out of touch with the hard working people of Bury South and the country as a whole," he added.
Answering questions in parliament, Johnson was defiant about the defection, saying his party would regain the seat.
"The Conservative Party won Bury South for the first time in generations under this prime minister with an agenda of uniting and levelling up and delivering for the people of Bury South," he said.
"And we will win again in Bury South at the next election under this prime minister."