It originally followed Rice Street from downtown St. Paul into the northern suburbs of the Twin Cities, shifting a northern termini between Interstate 35W and also the Lino Lakes Correctional Facility.

In the late 1990s, the route was cut back to end at Interstate 694 in Shoreview and then fully removed shortly after.

When a portion of Interstate 35W was constructed in 1966 and old U.S. 8 was moved to it at Lino Lakes, Highway 49 was then extended north along the former route of U.S. 8 and also replaced old State Highway 326, which served the Lino Lakes Correctional Facility.

In 1981, the route south of Highway 5 was renumbered 149 (Smith Avenue and Dodd Road).

The following list includes the major intersections of Highway 49 from 1981 to 1998, when the route was decommissioned.