The national death toll now stands at 375 and there are 680 Australians in hospital.
Mr Andrews said there were now 3,119 mystery cases in Victoria - 51 more than Thursday, which was a huge concern for the state.
"We've made the point, they are our greatest concern in some respects because we just can't work out the circumstances or individual where that infection began. That is a really big challenge and one that takes up so much time," he told media on Friday.
Chief health officer Brett Sutton said mystery cases during Melbourne's second wave accounted for about 20 per cent of overall infections, and 13 per cent of cases in regional Victoria.
Man in his 20s becomes Australia's youngest coronavirus death
A large proportion of mystery cases were occurring in the 20-29 age group, Prof Sutton said.
Mr Andrews said this was of little surprise.
"They are the people doing the shopping, working in permitted industries, those who are out and about for lawful reasons, as much as they are out and about breaking rules," the premier said.
There are currently 1,188 healthcare workers with active cases of coronavirus across the state.
Details emerge of 'patient zero'
Mr Andrews refused to be drawn into reports emerging on Friday over the identity of "patient zero" for the state's deadly second wave.
The Age newspaper on Friday reported a night duty manager at one of the quarantine hotels in Melbourne's CBD reported coming down with coronavirus on 25 May, presumably contracting it from a returned traveller.
According to leaked emails, seven guards and a small number of hotel staff and health workers were told to self-isolate after coming into contact with the manager.
Five of the seven guards reportedly tested positive soon after, spreading the disease to their families in Melbourne's northern and western suburbs.
Prof Sutton previously revealed genomic sequencing had linked a significant proportion, if not all of Victoria's second-wave cases, to breaches in hotel quarantine.
New COVID-19 testing sites in Victoria's regions
Meanwhile, the state government is launching new testing sites at Geelong, Ballarat and Bendigo after the cities collectively recorded more than 250 cases in the past 14 days.
Operating hours and staff will also be increased at pre-existing sites in the cities.
Mr Andrews said more data would develop a clearer picture of the outbreaks, while deputy chief health officer Allen Cheng hoped it would remove the need for Stage 4 restrictions in the regional centres.
Those awaiting test results will now also potentially be able to claim an extra $150, with the coronavirus hardship isolation payment increased to $450.
Prime Minister Scott Morrison said on Friday Australia was dealing with "complex challenges".
"The sad truth is, some days, we fall short. And other days, we don't. On some days, the pandemic gets the better of us, and on other days, it doesn't," he said.
"And I think we've got to have a reality check about this. There are no absolute guarantees in a global pandemic."
Mr Morrison said it would continue to be tough but Australians were up to the task.
"Some days, we wish better than has occurred. But I tell you what we do the next day - where there are lessons, where there are things to be acknowledged, you do that, and you set about the task the next morning."
Metropolitan Melbourne residents are subject to Stage 4 restrictions and must comply with a curfew between the hours of 8pm and 5am. During the curfew, people in Melbourne can only leave their house for work, and essential health, care or safety reasons.
Between 5am and 8pm, people in Melbourne can leave the home for exercise, to shop for necessary goods and services, for work, for health care, or to care for a sick or elderly relative. The full list of restrictions can be found here. All Victorians must wear a face covering when they leave home, no matter where they live.
People in Australia must stay at least 1.5 metres away from others. Check your state’s restrictions on gathering limits.
If you are experiencing cold or flu symptoms, stay home and arrange a test by calling your doctor or contact the Coronavirus Health Information Hotline on 1800 020 080. News and information is available in 63 languages at sbs.com.au/coronavirus
Additional reporting by AAP.