In the early 19th century, US 40 Alternate's path was improved as part of a series of turnpikes to connect Baltimore with the eastern terminus of the National Road in Cumberland.

The highway meets a CSX rail spur at grade while passing through an industrial area that extends to the southern city limits of Hagerstown at Kenly Avenue.

At the southern town limits of Funkstown, US 40 Alternate becomes Boonsboro Pike, which passes through farmland as it parallels Antietam Creek.

[1][4] US 40 Alternate enters the town of Boonsboro and its name changes to Main Street at its intersection with Maryland Route 68 (MD 68) (Lappans Road).

[1][4] US 40 Alternate's name changes to Old National Pike as it intersects the Appalachian Trail at the Washington–Frederick county line and begins its curvaceous descent of South Mountain into the Middletown Valley.

In the western part of the valley, the highway passes the Henry Shoemaker Farmhouse and intersects Mount Tabor Road, which parallels South Mountain north past the historic Daniel Sheffer Farm and Routzahn-Miller Farmstead.

In Spoolsville, US 40 Alternate crosses Catoctin Creek and meets Old Hagerstown Road, which passes the Bowlus Mill House.

US 40 Alternate passes the Stonebraker and Harbaugh-Shafer Building and intersects MD 17 (Church Street) within the Middletown Historic District.

At the base of the mountain, the alternate route temporarily expands to a four-lane divided highway through its half-diamond interchange with I-70, which has ramps to and from the direction of Frederick.

[1][4] The portion of US 40 Alternate between Frederick and Boonsboro roughly follows the Monocacy Road, a pack-horse trail blazed by settlers from Pennsylvania around 1730.

The trail connected Philadelphia, Lancaster, and Hanover with Winchester, Virginia, by way of what is now Taneytown, Frederick, Boonsboro, and Williamsport.

[5] The portion of the Monocacy Road from Frederick to Williamsport was used by the Braddock Expedition on its way from Alexandria to Cumberland to commence its ill-fated assault on Fort Duquesne.

[7] While the Monocacy Road as a whole was disused by 1794, the portion followed by US 40 Alternate remained an important connection between Baltimore and Western Maryland.

[9] The Maryland General Assembly used their powers again in 1821, agreeing to extend the banks' charters to 1845 if they would fund a turnpike in the gap between Boonsboro and Hagerstown.

[22][23] Surfacing of the remainder of the relocated National Pike was delayed by World War II; construction resumed in 1946 and the new highway opened in 1948.