The exact number of fatalities and injuries is not yet clear.
An unknown number of people have been transported to a local hospital for treatment following the incident.
New Mexico State Police say the semi was headed east when one of its tires blew, sending the rig across the median and into oncoming traffic where it slammed into the Greyhound bus.
Greyhound said bus schedule No. 1333 that left St. Louis Wednesday morning just before 9 p.m. was on Interstate 40 in New Mexico when it crashed head-on with a semi-truck.
Greyhound said the Phoenix, Arizona-bound bus carried 49 passengers.
A motorist who came upon the scene described it as chaotic as passengers were on the ground and people were screaming.
The NTSB said it's launching a go-team to investigate the crash. More information will be released when available. It was not immediately known what the conditions of the injured were.
Video from the scene shows the greyhound bus with extensive damage to the front end, as well as an overturned semi-truck and what appears to be boxes of produces scattered across the roadway. Police opened the eastbound lanes to let traffic through.
The National Transportation Safety Board will send investigators to the scene, Wilson said.