Curving from direct southeast to south-southeast, the road widens just before it makes a left turn to the northeast onto SC 170 across from a former section of that route.

SC 46 follows May River Road for approximately 8 miles relatively eastbound serving as a designated state scenic byway, with marsh vistas and live oak canopies providing a quintessentially Lowcountry feel to the drive.

Briefly turning northeast along the banks of the river that bears the road's name, it has one intersection with Buckwater Parkway, a four-lane divided highway serving developments in the Pritchardville-Hampton Lakes-Okatie area.

Upon entering Bluffton, the route runs along the northern edges of the original "square mile" or historic town center.

[6] By 1967, SC 46 was truncated at its current endpoint north of Bluffton; all east of point became part of US 278.