Locally, MSU-Meridian is directed by the Associate Vice President and Head of Campus in collaboration with various academic leaders in the areas of Arts and Sciences, Education, and Health Sciences. 

MSU Meridian started at what is now Hardin Hall on Meridian Community College's campus in a building originally constructed to house 350-450 students. Recognizing the value of MSU-Meridian to this region, the Lauderdale County Board of Supervisors spearheaded funding for a new building project in 1990. The state followed with an appropriation, and a private fund-raising campaign netted the remainder of the construction costs.

On August 29, 1993, the new Mississippi State University-Meridian facility was dedicated on a picturesque 26-acre campus across the street from its original location adjacent to Highway 19 North and College Drive in Meridian. This structure has become known as the College Park Campus.

Meridian community leaders once again joined with Mississippi State University in the late 1990s, developing a vision for the city’s long-abandoned Grand Opera House and the adjoining Marks Rothenberg and Newberry buildings in downtown Meridian. The renovation project gained major momentum in January 2000, when The Riley Foundation made the anchor $10 million contribution to restore the buildings. The contribution was made with a stipulation that Mississippi State University own and operate the center. Donations by local, state, and federal agencies followed, resulting in a $27 million restoration project that culminated in creation of the MSU-Riley Center, a performing arts center, conference center, and educational facility.

The MSU-Riley Center opened its doors in September 2006. The center includes a fully restored 1889 grand opera house theatre, a studio theatre, and 30,000 square feet of meeting space.

In 2009, The Riley Foundation again stepped in to assist the university, through a commitment of $4.5 million to expand the University’s presence in downtown Meridian. The gift included the donation of the Newberry Building, a historical landmark adjacent to the MSU Riley Center. Work on renovating the four-story building began in 2010. Renovation of the Newberry Building provided the University with an additional 20,175 square-foot academic facility that included classroom space and offices to house the MSU-Meridian Division of Business. The building was occupied in January of 2012, and the facility was dedicated and renamed the Deen Building.

In 2012, The Riley Foundation made another significant investment of $11 million to renovate the Kress Building slated to become the home of MSU-Meridian's Health Sciences program. Now known as the Rosenbaum Building, the facility houses state-of-the-art laboratories and classrooms as well as a new library made possible by a grant from the Phil Hardin Foundation. The Rosenbaum Building is home to the first publicly funded Master of Physician Assistant Studies program in Mississippi.

Success of the Master of Phsyician Assistant Studies program spearheaded a new purpose for the entire Riley Campus. In 2022, the university made a strategic decision in redirecting that campus to create innovative programs aimed at addressing critical needs of health disparity in the state. The Riley, Phil Hardin, and Broadhead Foundations have since committed almost $15 million toward the expansion of healthcare programs on the Riley Campus. Most recently, the university received Phase I approval from the Board of Trustees of the Mississippi Institutions of Higher Learning to launch the state's first Accelerated Master of Science in Nursing entry licensure program.