Emergency services were called to Newcastle Link Rd at the Transfield Drive roundabout following reports a vehicle had hit multiple people about 9.30am on Saturday.
NSW Police said 10 people were injured and treated at the scene before being transported to John Hunter Hospital.
A five-year-old girl and a 67-year-old man are in critical condition, while eight people, including a second five-year-old girl and a two-year-old girl, are in stable condition.
The driver of the vehicle, an 18-year-old, was arrested and taken to hospital for mandatory testing.
Newcastle Link Rd has been closed in both directions and is expected to remain closed for some time.
The Newcastle Knights bus was diverted via an alternate route following the incident, and the team has now left Newcastle ahead of the grand final in Sydney on Sunday.
NSW Premier Chris Minns said it was heartbreaking to see fans waving their team off involved in a terrible accident.
"My thoughts are with the families and friends of loved ones who have been involved or injured in the crash," he said in a statement.
"We've seen how this grand final has brought Newcastle together, and I hope the whole community remains united as we continue to respond."
Mr Minns thanked emergency services responding to the tragedy and urged people to drive safely this grand final weekend.
The Newcastle Knights said they were aware of the incident.
"Our thoughts are with everyone impacted by the incident, including those at the scene and their families," the club said in a statement.
It said it would not comment further as the incident was a matter for NSW Police.
Australian Rugby League Commission executive chairman Peter V'landys said in a statement the commission was working with police to understand the circumstances behind the incident.
Police are yet to speak about the cause of the incident.
In a post on social media, federal member for Hunter Dan Repacholi cited reports of a car doing a burnout before losing control.
Newcastle Mayor Gavin Morris said the crash was particularly upsetting given the environment of positivity and support heading into the grand final.
"We've been able to come together in an extraordinary way, and I believe now we will come together again in a new way," he told ABC News.
"We'll come together for the families and those injured, but we'll come together also for the Knights. It's obviously shifted the entire mood, but we'll get through this. "
The elation of the Knights' reaching Sunday's NRL decider prompted an avalanche of fan support in Newcastle.
Diehards waited in the rain for the team bus to return from Sydney after last weekend's 22-14 qualifying win over Penrith.
Thousands also showed up for team training during the week, while other Knights enthusiasts painted their houses in team colours.
A large crowd had lined Newcastle's streets on Saturday morning to farewell the players.
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