Mr Hazzard is the 12th NSW coalition MP heading for the exit at the March poll, leaving Premier Dominic Perrottet with a dozen spots to fill.
The long-serving MP has represented the seat of Wakehurst on Sydney's northern beaches since first being elected in 1991.
The 71-year-old is best known for his six years as health minister and managing the state's response to the COVID-19 pandemic, fronting the media daily to inform about the virus and urge adherence to recommended health measures.
Mr Hazzard ended speculation about his future on Monday night, weeks after a group affiliated with "teal Independents" announced it would mount a challenge in the blue-ribbon Liberal seat.
"As NSW health minister it has been the best of times and the worst of times," Mr Hazzard said in a statement.
The best times were working with "incredibly talented medical and non-medical staff in our health system" and delivering 180 new hospitals and health facilities.
"The worst of times came with COVID-19. When the pandemic began, we were bracing for an expected 25,000 deaths in NSW in the first year," he said.
"There were many anguished nights. What followed was a gruelling and a deeply upsetting time where rapid decisions had to be made to try and keep 8.5 million people safe from the virus."
Mr Hazzard broke down during a media interview on Tuesday, saying the past three years dealing with the pandemic had been "pretty horrible" and revealed the death of his younger brother led him to reassess his priorities.
"A personal situation occurred earlier this year - my younger brother died.
"It's very big, yep," told Sydney radio 2GB.
"I'm going to enjoy life. That's all I'm determined to do."
Behind the scenes during the lockdowns, he was also dealing with threats that required lengthy periods under special police protection when he left the house, as well as security at his home.
"It's not very pleasant," he said.
The former teacher and lawyer has been in cabinet since 2011, including as attorney-general and minster for planning, justice, social housing, community services and health.
Premier Dominic Perrottet described Mr Hazzard as a "tireless and committed advocate for people right across our state".
"Our state is a better place thanks to Brad's significant contribution," he said.
