Drivers were caught in tailbacks following the collision which happened near junction 11 southbound at about 1.30pm on Monday.
The road was closed for about five hours while emergency services dealt with the crash.
One driver at the scene said she waited for more than an hour.
It remains unconfirmed whether or not there were any injuries.
An updated statement on Traffic Scotland confirmed the road reopened at 6pm.
The full statement read: “M74 now open southbound - all lanes running. Traffic remains heavy and will take time to clear. Delays approximately 1 hour 5 mins.”
A spokesman for police said: "Police were called around 1.30pm on Monday, June 7, 2021 following the report of a two vehicle road crash on the M74 southbound.
"Emergency services are in attendance and there are no details on injuries at this time."