In Maryland, Hands Across America will follow Rte. 40 from Delaware into Baltimore. The line will travel west on Erdman Avenue to 32nd Street, west on 32nd Street to 33rd Street, west on 33rd Street to Charles Street, then south on Charles Street to Pratt Street. From Pratt, the route goes west to Fulton Avenue, south on Fulton to Wilkens Avenue, west on Wilkens to Southwestern Boulevard (Rte. 1) and then south on Rte. 1 to Hyattsville. From Hyattsville, the line travels west on Jefferson to 38th Avenue, south on 38th Avenue to Rhode Island Avenue (Rte. 1) and south on Rhode Island Avenue to the Washington border.

Exiting the District, the route travels north on Wisconsin Avenue (Rte. 355) to Old Georgetown Road (Rte. 187) in Bethesda, north on Rte. 187 back to Rockville Pike (Rte. 355) and north on Rte. 355 to Frederick.

From there, the line continues north on Market Street to West Patrick Street (Rte. 144), west on Rte. 144 to Baltimore Pike (Rte. 40) and west on Rte. 40 to Hagerstown. In Hagerstown, the line travels west on Franklin Street (Rte. 40) to Jonathan Avenue (Rte. 11), north on Rte. 11, becoming Pennsylvania Avenue and Middleburg Pike, to the Pennsylvania border.