According to the Bureau of Meteorology, humid conditions will make the maximums for Friday though to Sunday feel considerably warmer than the temperatures suggest.
The current forecasts are for tops of 29 and 33 for the city on Friday and Saturday. On Sunday, the city can expect a scorching 39 degrees, with some suburbs possibly climbing into the low-40s
"I wouldn't want to be playing the men's tennis final on Sunday," said Chris Godfred, a senior bureau forecaster, referring to the Australian Open event. "It won't be very pleasant."
Along with the high temperatures, the dew point - the temperature at which air becomes saturated with water - could rise into the low 20s, making it harder for the body to lose heat through perspiring.
Among comparisons could be a period in 2011, when tropical-like deluges flooded parts of Victoria and made conditions very sticky in Melbourne.
"What we're forecasting for over the weekend would approach those values though probably not exceed them," Mr Godfred said.
Blair Trewin, a senior climatologist at the bureau, said Melbourne has never recorded a combination of 35 degrees and a 20-plus dew point reading.
"Broadening to 35 and 18 [degrees, dew point], there are four separate events where that has occurred," Dr Trewin said.
Two of them were during last summer, and the others back in 1993, when two days "coincided with the notorious Guns n' Roses concert at Calder Park", he said.
Jamie Goldie, a researcher at the Climate Change Research Centre based at the University of NSW, said projected dew points at the weekend combined with the temperature forecasts suggest conditions could be as severe as those on Black Saturday in 2009 - the state and city's hottest day.
The humidity and heat this weekend could produce a "killer combo", particularly for those out in the sun, he said.
The so-called wet bulb globe temperature gauge, which takes into account temperature, humidity, sunshine and even wind, could approach or exceed the highest levels recorded in Melbourne, Mr Goldie said.
Organisers at the Australian Open will be monitoring conditions closely as a 32.5-degree web bulb temperature reading is enough for the referee to suspend play.
During last week's heat, when the temperature reached 40.2 degrees at Melbourne Park on Friday, the wet bulb reading peaked at 31.1, according to Tennis Australia.
While professional tennis players and other sportsmen and women would have access to ice vests or cold showers before their matches, the same may not be true for the general public.
"It's not going to be a great time to exercise," Mr Goldie said, adding this weekend would be a good time to check on friends and relatives who may be vulnerable to heat stress.
Mr Godfred described the weather as "insufferable", with temperatures on Saturday night likely to remain in the mid- to high 20s until about midnight.
After cooling a bit by Sunday morning - a minimum of 23 is tipped - the mercury will climb again from dawn.
"Those conditions can be even potentially deadly in terms of heat stroke because that sweat mechanism is what allows the body to cool down," Mr Godfred said.
Relief will also take some time to arrive.
"We won't see a wind change through until the early hours of Monday morning," Mr Godfred said.
Researchers say climate change may make events such as this weekend more likely.
"We're going to see more extreme days in the future," with hotter temperatures "a no-brainer", Mr Goldie said.
However, just how humidity will change for cities such as Melbourne remains "an area of active research", he said.
The story 'Killer combo' of heat, humidity lining up for Melbourne first appeared on The Sydney Morning Herald.