The China Eastern Airlines Boeing 737 was flying from Kunming to Guangzhou when it came down in hills in Guangxi province and caught fire.
It is feared there are no survivors, but the number of casualties – and reason for the crash are not yet known.
Chinese airlines generally have a good safety record: the last major accident took place 12 years ago.
Rescue crews have been sent to the crash site and say a fire in woods caused when the aircraft came down has been put out.
Videos widely shared on social media that appear to be taken by locals show plane debris strewn around the hills, and a fiery blaze and smoke billowing from the crash site.
The country’s last major plane accident was in August 2010, when a flight from Harbin crashed in Yichun killing 42 people.
China Eastern is yet to comment on the crash, or respond to queries, but it has greyed out its logo on its Weibo account and also changed its website to black and white- a sign of mourning, local media reported.
China’s Civil Aviation Administration said it had also dispatched its investigators to the scene.
Flight MU5735 left Kunming at 13:11 local time (05:11 GMT) and was scheduled to arrive in Guangzhou at 15:05.
Flight tracking sites report the plane was in the air for just over an hour, and was nearing its destination when it went down in Wuzhou.
According to FlightRadar24 data, the last sourced information on the flight showed it ended at 14:22 local time, at an altitude of 3,225 ft.