The bus carrying 19 interstate tourists crashed on Monday afternoon near Hermannsburg, 125km west of Alice Springs, Northern Territory police say.
"They were doing a day tour out of Alice Springs and they were on their way back," Detective Senior Sergeant Michael Schumacher told reporters on Tuesday.
"It's a major road with a lot of people travelling up and down it. It's a terrible tragedy. Someone has lost their life while holidaying in central Australia."
A 69-year old-male passenger died at the scene.
Four other passengers, including three women aged 62, 67 and 70 and a man aged 60, were taken to the Alice Springs Hospital with multiple serious injuries.
All remain in hospital in a stable condition. The 67-year-old woman is in intensive care.
A 68-year-old man was also taken to the same hospital and treated for minor injuries.
The driver and remaining passengers suffered cuts and bruising. All were treated at a clinic in the remote Aboriginal community by medical staff that travelled from the Alice Springs Hospital, and paramedics.
The incident is understood to have happened on Larapinta Drive, 5km east of Hermannsburg, after the tourists had visited a national park.
"Fatal crashes are always confronting," Det Snr Sgt Schumacher said.
The NT police major crash unit and NT Worksafe are investigating.
It's not clear if all the passengers were wearing seatbelts.
Police said earlier that it appeared the bus driver had lost control.
Det Snr Sgt Schumacher said there was no information to suggest another car or an animal was involved.
Several fatal crashes have previously happened in the area.
Hermannsburg is also known as Ntaria and has a population of about 600 people.
It's known for being the home of Aboriginal artist Albert Namatjira and a National Trust-listed historic precinct due to its German-style mission buildings dating from the 1870s.
The community is also near the Finke Gorge and Tjoritja/West MacDonnell national parks.
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