Emergency services were called to the intersection of the Bruce Highway and Rangemore Road at Gumlu in the Whitsundays region about 4pm AEST on Thursday after reports of a crash involving a bus with 29 people on board.
One person died from their injuries, Queensland Police said.
Two passengers were being treated for significant head injuries and multi-system trauma.
One person was trapped under the bus, according to the Queensland Fire Department.
Eleven ambulances as well as two helicopters and a Royal Flying Doctor Service plane attended the scene.
No other vehicles are believed to have been involved in the incident.
The bus driver, a 70-year-old Mackay man, was taken to hospital with minor injuries.
Several passengers were taken to Townsville, Ayr and Bowen hospitals.
The road was closed in both directions and long delays were expected.
Police are appealing for witnesses to come forward.
The Bruce Highway has long been considered one of the most dangerous roads in Australia.
Stretching from Brisbane to Cairns, the highway is used by more than 100,000 vehicles every day, according to NRMA.
Of the 302 people killed on Queensland roads in 2024, 41 died on the Bruce Highway while another 7500 were hospitalised after driving on the road, according to data from the state's Department of Transport and Main Roads.
The stretch from the Sunshine Coast to Gympie is widely regarded as the most perilous part of the highway.
More than 66 per cent of people believe there are not enough overtaking lanes on the highway while a third of respondents said they avoided travelling on the Bruce during family holidays, according to a 2024 NRMA survey.
In a bid to bolster driver safety, the federal government earmarked an extra $812 million for the second stage of upgrades to the Bruce Highway after delivering the budget on Tuesday.
This added to $758 million already delivered during stage one.
