The opposition foreign affairs spokesman will quit at next year's federal election, and says he will take a "new commercially oriented direction".
He ruled out lobbying, government relations or commentary.
Referencing an ancient Persian proverb, the South Australian said "now it is time for my parliamentary service to also pass".
"Some will be kind enough to be disappointed to see me go ... but some, to them, I am sorry, especially for those who feel that I'm letting them or the team down at this time.
"It is always better to go when there are some wishing you to stay, and none of us is irreplaceable. Now is the right time for me, for my family and for new career pathways."
Senator Birmingham served as trade, finance and education ministers in coalition governments. (Lukas Coch/AAP PHOTOS)
Senator Birmingham entered parliament in 2007 and has served as trade, finance and education ministers in coalition governments under Malcolm Turnbull and Scott Morrison.
The leader of the Liberal moderates faction is respected across the parliament, and with 17 years of experience is seen as a loss to the party.
The 50-year-old backed in the former Morrison government's handling of the COVID-19 pandemic.
He took aim at China's "abuse of power" when it slapped punitive trade sanctions worth $20 billion on Australian products.
"Australians should be proud that our businesses, our economy and our nation withstood that attempted coercion," Senator Birmingham said.
Simon Birmingham rejected perceptions that parliament was a universally toxic workplace. (Mick Tsikas/AAP PHOTOS)
He rejected the "perceptions" peddled by some in parliament that it was a universally toxic workplace.
"Whilst we should never tolerate the type of behaviours that led to the Jenkins report, the whole should not have their experiences universally besmirched," he said.
The senator said little was gained by culture wars which risked social cohesion in a country like Australia.
"The rise of the global rise of populism and divisive tribalism peddled by ideological extremes troubles me," he said.
Thanking his wife and children, Senator Birmingham fought back tears, as his family watched on from the public gallery.
"Those of you who have the honour of continuing in this place, carry a great responsibility.
"I wish you well, do good, make a positive difference. Thank you, and farewell."
Simon Birmingham and Labor counterpart Penny Wong have great respect for each other in the Senate. (Mick Tsikas/AAP PHOTOS)
He received a standing ovation after his speech, and Foreign Minister Penny Wong leant over to shake his hand.
Opposition Leader Peter Dutton thanked Senator Birmingham at the end of Question Time.
"Birmo has a young family and I know he's going to look forward to spending more time with them, and he's given an enormous amount to our country," he said.
Prime Minister Anthony Albanese said the Liberal senator had "very broad respect right across the parliament, and he certainly has my personal respect".
"He's someone who is someone of integrity, who is easy to deal with and to get things done.
"So to Simon and Courtney and their family, it is understandable that he's made this decision, but I wish him all the very best," he said.
24°C