The vehicle was travelling along Chapel Road in Muckatah, about 10km south of Cobram near the Victorian-NSW border, when it lost control about 5pm on Monday.
A 17-year-old boy, a 34-year-old man, 51-year-old woman and 45-year-old woman died at the scene.
Four teenagers aged between 16 and 18 were rushed to hospital.
All remain in a serious condition.
A 39-year-old man remains in hospital under police guard.
Police believe those involved in the crash were working in the area and are from overseas.
Victoria Police's Major Collision Investigation Unit rushed to the scene on Monday evening.
Acting Superintendent Ash Mason said a motorist alerted police after witnessing the crash.
"It's absolutely tragic," he said. "We've got four lives lost and, as we know, we're only 10 days away from Christmas."
Premier Jacinta Allan praised the work of emergency services and expressed sorrow for the family and loved ones of those killed and injured.
"It's a horrific accident," she told reporters on Tuesday morning.
"And to happen so close to the Christmas period so close to the end of school, where families are looking forward to spending time together, it's a terrible tragedy."
The road has reopened as police continue to investigate the cause of the crash, as well as the identities of the victims and their relationship to one another.
Google Maps images from July showed no posted speed signs along the road, which is narrow with gravel on either side to allow vehicles travelling in opposite directions to pass.
Five people were killed in a crash at nearby Strathmerton on April 20, 2023.
Driver Christopher Joannidis was warned by police about dangerous roads in Strathmerton minutes before the crash.
He drove off, crossed over three sets of rumble strips and ignored give way signs as he drove onto the Murray Valley Highway from Labuan Road without stopping.
His Mercedes Benz sedan crashed into a Nissan Navara ute with five people and a dog inside, pushing it into the path of a truck towing two trailers of milk.
Ute driver Deborah Markey, 62, her dog Sophie and four farm workers from Taiwan and Hong Kong staying at her home - Zhi-Yao Chen, Pin-Yu Wang, Wai Yan Lam and Hsin-Yu Chen - all died instantly.
Joannidis pleaded guilty to five counts of dangerous driving causing death and was jailed on January 23 for up to five-and-a-half-years, with prosecutors since appealing his "manifestly inadequate" sentence.
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