The station opened on August 27, 2015, eight months after Amtrak's Vermonter service was re-routed to the Connecticut River Line through the Pioneer Valley.

The Connecticut River Railroad opened to passenger service between Springfield and Northampton in late 1845; trains reached Deerfield in August 1846, Greenfield in December 1847, and the junction with the Central Vermont Railway in January 1849.

[5] Holyoke's original train depot, which was located near Dwight and Main Streets, was a modest wooden structure that served both passenger and freight needs.

[9] In May 2009, as the building sat littered with graffiti and falling into disrepair, it was purchased from a private owner by the City of Holyoke's Gas & Electric department.

[9] In August 2014 the Holyoke Office of Planning & Economic Development issued a report detailing a number of potential new uses for the former Connecticut River Railroad station building.

Proposed potential uses were divided into four broad themes: Food Uses, Collaborative Workspaces & Commercial Uses, Community & Cultural Uses and Academic Engagement & Educational Uses.

[18] The new Depot Square Railroad Station, which cost approximately $3.2 million, includes a 400-foot (120 m)-long high level platform, 170-foot-long canopy, and a waiting area and staircase facing Dwight Street.

[2] On August 30, 2019, Amtrak extended two daily New Haven–Springfield Shuttle round trips (branded as the Valley Flyer) to Greenfield as a pilot program.