It runs south-to-north from CR 75 in Smith Point County Park (part of the Fire Island National Seashore) to New York State Route 25A (NY 25A) near the border of Shoreham and Wading River.

The route then proceeds northward to cross the Great South Bay on a bascule lift bridge and soon onto mainland Long Island.

After crossing onto the mainland, CR 46 becomes a divided four-lane boulevard with a wide grass median past several bayside residential communities.

Bending north through several residential neighborhoods of Smith Point, the route crosses into the community of Shirley near Coraci Boulevard.

[3] CR 46 crosses northeast through Shirley, passing a large commercial strip through the village and an at-grade interchange with Stuart Road.

The parkway condenses to six lanes for a short distance northwest of the junction before reaching a cloverleaf interchange with NY 27 (Sunrise Highway) in Shirley.

Crossing Longwood Road/Princeton Avenue (which provides access to Brookhaven National Laboratory), the parkway bends northeast through a mix of wooded and residential sections.

Near the vicinity of the Montauk Branch of the Long Island Rail Road, a series of intersections known as "The Circles" were built on the south side of the tracks.

Camp Upton Road was originally part of CR 46, until NY 27 (Sunrise Highway) was extended through the area in 1957, and an interchange was built for a realigned section.

CR 46A was the original designation for the alignment along the west side of Brookhaven National Laboratory between Yaphank-Moriches Road and south of the interchange with NY 25.

The intersection at NY 25A, which was originally proposed to be an interchange, now features channelized turns and two separate traffic light controls due to the extremely wide median of CR 46.