OR 221 begins, at its southern terminus, at an interchange with OR 22 in Salem, just west of the Marion Street Bridge.

This intersection is a partial interchange connecting OR 221 directly only to and from downtown Salem.

To connect to OR 22 westbound one must turn onto Edgewater Street and travel about a mile to the highway entrance.

One must turn left (north) there, turn right (east) onto 7th Street, continue to Taggart Drive, and finally make a left (north) onto Wallace Road (OR 221).

From the intersection with OR 22 in Salem the highway heads northwest, as an urban expressway known locally as Wallace Road; upon leaving the Salem area it becomes a 2-lane country road, which roughly parallels the Willamette River to the east.