The state highway runs 19.08 miles (30.71 km) from U.S. Route 40 (US 40) in Riverside north to MD 165 in Pylesville.

The state highway initially heads southeast from US 40, then curves clockwise 180 degrees toward the northwest to cross over US 40 and CSX's Philadelphia Subdivision railroad line.

MD 543 heads northwest as Riverside Parkway, a partially controlled-access two-lane undivided highway between residential subdivisions.

[1][2] MD 543 continues northwest and traverses James Run within the Harford Furnace Historic District.

The state highway passes the historic homes Fair Meadows and Best Endeavor in the rural community of Creswell.

After intersecting MD 136 (Calvary Road), MD 543 continues northwest as Fountain Green Road, which crosses over a branch of Bynum Run and passes the historic homes Mount Adams and Broom's Bloom.

Just before crossing Deer Creek, the state highway intersects Walters Mill Road, which provides access to the historic D. H. Springhouse.

[8] Another predecessor highway, MD 634, was under construction by 1936 and completed by 1938 from Creswell to Fountain Green.