Paul Papalia, the Western Australian Minister for Corrective Services and member for the seat of Secret Harbour, south of Perth, quit politics on Monday.
"This isn't what I'd planned," he told reporters.
"One of my immediate family members has been diagnosed with a serious illness."
Premier Roger Cook said his party will have to work hard if it wants to retain the seat, which is made up of working and middle-class families.
"It's going to be really tough," he said.
"We're not taking anything for granted.
"We know that during a by-election, there's heightened debate and there's increased focus, and as a result of that, we're going to have to fight for our lives on this one."
Mr Papalia, a navy veteran who entered politics in 2007, won Secret Harbour for Labor in 2025, polling 61.5 per cent of the two-party preferred vote amid a 28.5 per cent swing away from the party.
The Liberals won 28.5 per cent of the vote, recording a swing of 9.8 per cent to the party.
One Nation, which polled 8.4 per cent of votes in 2025, with a 6.3 per cent swing to it, confirmed it will run a candidate.
WA One Nation Leader Rod Caddies said Labor has treated Secret Harbour as a safe seat and voters aren't happy.
"They've been missing in action, and we're going to sink Labor in Secret Harbour," he told AAP.
The party has a short list of potential candidates, but no one has been officially nominated to run.
"We want to make sure that we don't leave any stone unturned in getting the very best," Mr Caddies said.
Ms Hanson could also make an appearance on the hustings once the by-election date is announced.
"I certainly will be asking her if she can make herself available," Mr Caddies said.
Political commentator Peter Kennedy said Labor will "lose some paint" in the poll but is likely to retain the seat.
"The big question for Labor is how much support it will lose," he told AAP.
"It's got a fair buffer, but things are a bit volatile at the moment, so I think there would be a bit of nervousness all around the traps."
The by-election's "moment of truth" will be how many votes One Nation gets and how much of the struggling Liberal Party vote it can take.
"It'll be a test for (WA Liberal) Basil Zempilas and his leadership," he said.
"It's also a big test for One Nation, whether the swing we've been seeing to One Nation is reflected in actual votes."
Mr Papalia is the longest-serving MP in WA's Legislative Assembly and was also Minister for Emergency Services; Defence Industries; Veterans; Racing and Gaming.
He was elected to the seat of Peel in 2007 in a by-election, then re-elected to the new seat of Warnbro, which later became Secret Harbour, holding it until he announced his retirement.
His last day in Parliament will be July 10.
His resignation also means the premier will need to reshuffle his cabinet, with the Labor Caucus to meet on Friday at noon.
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