After almost 17 years in the upper house, Mr Wade will retire before state parliament resumes on February 7, saying it's the "right time for a change for the Liberal party and for me".
"It has been a privilege to serve the people of South Australia," Mr Wade said in a statement on Saturday.
"It was an extraordinary honour to serve as health minister and chair the national health minister's meeting during a once-in-a-century pandemic.
"I am looking forward to exploring new opportunities to serve in the years ahead. Thank you to everyone who shared this journey with me."
Liberal Leader David Speirs said Mr Wade's political career had been built on hard work and dedication.
"Stephen is renowned as a hard worker, during the COVID-19 pandemic especially. His 4am messages to colleagues were legendary," Mr Speirs said.
"There is no doubt that his role in the former Liberal government's handling of COVID-19 was key to South Australia safely navigating the pandemic, in comparison to other jurisdictions.
"Lives were saved, the disruption to the community was minimised and the state was able to return to normal life as quickly as possible."
Mr Wade's official eight-year term in the Legislative Council was due to expire at the next state election in 2026.
His departure gives the Liberal opposition the opportunity to fill the casual vacancy with Mr Speirs expected to push for the seat to be taken by a woman.
Mr Wade, 62, was first elected to parliament in 2006 and served as health minister throughout the four-year term of the previous Liberal government.
He has served on the back bench since the Liberals lost the state election in 2022 to the Labor party.
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