Joint patrols with Burma and Laos started on Saturday morning, China’s state media reported.
Personnel from Thailand are expected to join the operation further downstream, possibly on Sunday.
The patrols are a response to the killing of 13 Chinese sailors travelling on the river in October.
The four-nation deployment aims to fill a security vacuum in the Golden Triangle region, an area notorious for drug-trafficking.
China’s booming trade along the Mekong was suspended after the attack on 5 October left the bodies of the Chinese crew members floating in the water.
Drug smugglers were initially suspected of the attack, but nine Thai soldiers were subsequently detained.
It is not yet clear how they will link up with their Burmese, Lao and Thai counterparts, how far along the Mekong the patrols will go, or if officers from one country will be able to perform arrests in others’ territorial waters.
China’s declared policy of non-interference in other countries’ affairs has shifted as its economic horizons expand.