The crash is one of two on the same stretch of road within less than two hours, with about 20 or more people involved across the two separate incidents.
Both crashes involved three vehicles each and have left emergency services and members of the public reeling.
One woman posting on social media after the incident urged everyone to stay safe.
"I never imagined myself doing CPR on someone on the road," she said.
The earlier crash happened between Hayman Road and Tekapo Canal Road about 1.30pm Saturday.
A large number of emergency service staff, including three rescue helicopters responded, police district operations and support manager Inspector Craig McKay said in a statement.
"Despite the best efforts of those first at the scene, three people were unable to be saved," he said.
"Several of the injured were trapped in the wreckage and needed to be cut out."
Three of the injured were flown to hospital in a serious condition and two, assessed as moderate, were taken by ambulance, St John confirmed.
"One of the deceased was riding a motorcycle while the two others who lost their lives were travelling together in one of the cars," McKay said.
"We are in the early stages of the investigation to determine what caused this tragic event."
The Serious Crash Unit attended the scene into the evening.
"A complex and lengthy investigation lies ahead of us."
Police closed State Highway 8 and it is not expected to reopen until late in the evening. Motorists face a lengthy detour and are encouraged to delay travel.
"Crashes of this nature are incredibly confronting, and we are arranging support for those members of the public who were first at the scene and tried their best to save lives," McKay said.
"We can’t thank them enough.
"Any fatal crash, but particularly one where multiple people have lost their lives, is confronting even for veteran emergency service personnel.
"We will also be making sure our staff at the scene have the support they need following this horrific event.
"Only 90 minutes after this crash, police were alerted to a second three-vehicle crash a short distance away, at the intersection of State Highway 8 and Tekapo-Twizel Road."
One person received serious injuries and nine others suffered minor-to-moderate injuries in that incident.
Enquiries into the cause of the second crash are ongoing.
"We want to ask every motorist on the roads this weekend to take extra care."Please take your time, have plenty of breaks and drive to the conditions. Crashes like this show how easy it is for things to go horribly wrong."
A St John spokesperson said they sent 11 resources to the scene of the first crash, including four helicopters, three ambulances, one rapid response unit, one prime vehicle, one first response unit, and one manager.
"We have assessed and treated five patients so far. Three in a serious condition have been airlifted to Christchurch Hospital," they said earlier.
"We have two patients in a moderate condition via road to Timaru Hospital."
The spokesperson said they assessed six people, and there may have been some they were not required to transport. They referred further queries to police.
Waka Kotahi said on social media the road was likely to remain closed "for several hours, possibly well into this evening".
The fatal crash has sent this year’s Easter road toll from zero to three.
The road toll is measured from 4pm on Thursday, March 28 and ends at 6am Tuesday, April 2.
Before today’s crash there had been no fatal crashes within that time period.
