Imagination Station was incorporated as a non-profit organization in 1988. After three years of intensive community-wide effort, the 25,000 square-foot former U.S. Post Office and Federal Court House was converted into a new museum space and Imagination Station opened its doors on February 15, 1992. The project received broad support, including funding from the City of Wilson and Wilson Chamber of Commerce, and was recognized for its effective reuse of an historical property.

Since its opening, Imagination Station has brought hands-on science education to more than 475,000 people in the Wilson community and eastern North Carolina. Teachers soon recognized the Museum as an essential educational resource to augment classroom studies for their students. The Museum has furthered its reach into eastern North Carolina through its popular Science on Wheels outreach educational service, which serves more than 11,000 school children each year. Additionally, beginning in 1998 the Museum has provided science enrichment programs to preschool children at daycare centers in Wilson, Johnston and Wayne Counties, funded by North Carolina's Smart Start Program. In 2002, Imagination Station was approved to serve as a NASA Satellite Educator Resource Center (ERC) for eastern North Carolina. Satellite ERCs provide NASA educational materials that are available to teachers, free of charge.

On January 14, 2000, a severe fire caused damage to all five floors of the historic building, destroyed many exhibits and killed most of the Museum's animals. As part of the two-year rebuilding process, Imagination Station addressed safety and building code issues and enhanced the visitor experience by improving traffic flow throughout the building. The Museum reopened its doors to the public in September 2002, after more than 2 years serving the public from a temporary location.

In October 2003, Imagination Station's Executive Staff and Board participated in the Blue Cross Blue Shield Healthy Communities Program to consider ways that the organization could operate more effectively and to examine its role in the community. As a result of this program, Imagination Station held a Board Retreat in January 2004 and began developing its first long-range plan since 1996. Staff and Board worked to realign the mission and goals of the Museum, as well as to adopt best practices to allow the Board of Directors to function more efficiently. In March 2005 the Museum was awarded one of three Blue Cross Blue Shield Foundation of North Carolina Best Practices In Non-profit Management Awards.

The City of Wilson, Wilson County and the corporate community have all been supportive of Imagination Station in recent years with significant contributions towards both operating and capital costs. In 1998 Imagination Station was awarded a prestigious MINDS (Minorities' Interests Nurtured and Developed in Science) grant from the Burroughs Wellcome Foundation (Research Triangle Park, NC). The MINDS program was developed to increase science interests among minority groups, giving students the opportunity to engage in science enrichment activities and conduct real scientific research under the mentorship of working scientists in the region.

In 2009 Imagination Station Science Museum was honored to be awarded a $150,000 grant from the Institute of Museum and Library Services (IMLS) Museums for America program. Museums for America is the nation's largest federal funding program for museums. Reviewed by panels of professional peers, these grants are highly competitive. The Museum's grant has funded a new exhibitions master plan and a portion of the first phase of exhibition fabrication. This project helps to redefine the Museum by transforming the nature of its educational services and visitor experiences. It is the first IMLS award received by Imagination Station.