Ed Vaizey says he will not stand for re-election to focus on his passion for the arts and creative industries.
The former culture minister said the decision to stand down as an MP was “one of the hardest I have ever taken”.
Mr Vaizey said he would “remain an enthusiastic supporter” of Prime Minister Boris Johnson.
The MP for Wantage had the Conservative whip returned to him last month after losing it for backing efforts to block a no-deal Brexit.
In his resignation letter to the prime minister, Mr Vaizey said he believed “now is the right time to move on”.
“I am passionate about the arts, our creative industries and technology and I want so specialise in these sectors”, he added.
Mr Vaizey, who represented the constituency of Wantage since 2005, thanked Mr Johnson for returning the whip to him, “despite our temporary differences”.
“I will be your friend and ally wherever I end up and whatever I may do”, he added.
Bethan Nimmo, BBC Radio Oxford political reporter
Ed Vaizey’s political career has been bit of a rollercoaster lately.
He had the Tory whip removed for voting against the government on Brexit in September – but he was suddenly welcomed back into the party at the end of last month as the general election loomed.
Now he’s announced he won’t be standing. That’s likely to mean his former seat becomes a key target for the Liberal Democrats.
They saw big gains in the area in the local election – gaining 22 seats in what was the previously Conservative stronghold of the Vale of White Horse.
In a very pro-remain area, where many are employed in science and research, the Tories may struggle to find a warm welcome for their promise to “get Brexit done”.
Mr Vaizey previously served as culture minister in David Cameron’s government and during the coalition years prior.
After he was expelled along with 21 Tory MPs in September, he said would consider standing as an independent against an Tory candidate.
The MPs were thrown out of the parliamentary party for backing legislation designed to stop the UK leaving the EU without a deal – the so-called Benn Act.
But he was readmitted to the party with nine other rebels shortly before MPs backed the prime minister’s plan to hold an early election on 12 December.
Other Conservative figures who are leaving Parliament include Philip Hammond, Amber Rudd, Nicky Morgan, Rory Stewart and Margot James.