Heavy rains caused a stretch of road running from Meizhou city towards Dabu county to cave in at around 2:10 am on Wednesday (1810 GMT Tuesday), according to state news agency Xinhua.
Over 20 vehicles careened into the nearly 18-metre-long (60-foot) gash in the tarmac and plummeted down the steep slope below.
Guangdong, a densely populated industrial powerhouse, has been hit by a string of disasters attributed to extreme weather events in recent weeks.
The storms have been much heavier than expected this time of year and have been linked to climate change.
China is the biggest emitter of the greenhouse gases that contribute to climate change but has pledged to reduce emissions to net zero by 2060.
- 'All-out' efforts -
The highway collapse had caused the deaths of 48 people as of 2 pm on Thursday, Ma Zhengyong, the secretary of Meizhou's Communist Party committee, said at a press briefing.
The toll was up from 36 people on Thursday morning.
"In addition, there are three people whose DNA is undergoing further comparison and confirmation," Ma said.
It was not immediately clear whether those three victims were included in the toll of 48.
A further 30 people were injured, with one in a "severe" condition and the rest stable, said Liu Lebin, the deputy party secretary of Meizhou's health bureau.
Footage by state broadcaster CCTV showed excavators digging through the muddy hillside below the collapsed road.
Nearby, a crane lifted charred, wrecked vehicles onto a lorry as people watched from behind a cordon.
State media called the road collapse a "natural geological disaster" caused by the "impact of persistent heavy rain".
President Xi Jinping ordered officials to "go all-out in on-site rescue work and treatment of the injured, and arrange for the management of risks and hidden dangers in a timely manner", CCTV said on Thursday.
A city official said adverse weather conditions, the risk of secondary disasters and the large number of trapped, burned and buried vehicles were complicating rescue and recovery efforts.
Over 570 people have been dispatched to help with the rescue operation, the official added.
The provincial government has "mobilised elite specialised forces and gone all out to carry out... search and rescue", according to Xinhua.
An official notice on Wednesday advised that part of the S12 highway was closed in both directions, requiring detours.
- More disasters likely -
Parts of central and eastern Guangdong have received up to 600 millimetres of rain in the last 10 days, three times the amount normally expected at this time of year, the national weather office said Thursday.
Up to 120 millimetres more rain was forecast for the province's southwestern areas on Thursday, alongside further downpours across southern China until Sunday.
The conditions "raise the risk of disasters, especially geological disasters, which have a certain lag time", the weather office said.
The emergency management ministry also warned that persistent rain would make such disasters more likely.
Officials have warned people to plan journeys carefully during the May public holiday, which runs until Sunday.
Massive downpours in Guangdong last month sparked floods that claimed four lives and forced the evacuation of more than 100,000 people.
And last week, a tornado killed five people when it ripped through the megacity of Guangzhou.
Landslides and other disasters are common in China, particularly in mountainous areas.
At least 44 people were killed when a landslide buried village homes in the southwestern province of Yunnan in January.
And heavy rains sparked a similar disaster near the northern city of Xi'an last August, causing the deaths of more than 20 people.
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