U.S. Route 50 Business is a business route of U.S. Route 50 in the U.S. state of Maryland. The highway runs 6.88 miles (11.07 km) from US 50 on the northwest side of Salisbury to US 13 and US 50 on the east side of Salisbury in central Wicomico County. US 50 Business is a four- to six-lane divided highway within and on either side of the central business district of Salisbury, where the highway intersects MD 349, US 13 Business, and MD 346. US 50 Business west of MD 349 is a mid-1950s upgrade of the original highway entering Salisbury from the northwest. The business route between MD 349 and MD 346 was a relocation of US 50 from Main Street built in the early 1960s. East of MD 346, US 50 Business is part of the relocation of US 50 between Salisbury and Berlin completed in the mid-1960s. US 50 Business was designated when the US 50 portion of the Salisbury Bypass was completed in 2002.

U.S. Route 50 is a major east–west route of the U.S. Highway system, stretching just over 3,000 miles (4,800 km) from West Sacramento, California, east to Ocean City, Maryland, on the Atlantic Ocean. In the U.S. state of Maryland, US 50 exists in two sections. The longer of these serves as a major route connecting Washington, D.C., with Ocean City; the latter is the eastern terminus of the highway. The other section passes through the southern end of Garrett County for less than 10 miles (16 km) as part of the Northwestern Turnpike, entering West Virginia at both ends. One notable section of US 50 is the dual-span Chesapeake Bay Bridge across the Chesapeake Bay, which links the Baltimore–Washington metropolitan area with the Eastern Shore region, allowing motorists to reach Ocean City and the Delaware Beaches.