The road passes through the communities of Hampden, Medfield, Cross Keys, and Mount Washington in the city, and Brooklandville and Butler in Baltimore County.

[1][4] West of Maryland Avenue, Lafayette Street and Lanvale Street merge into two-lane undivided Falls Road, which curves northwest and briefly parallels Amtrak's Northeast Corridor railroad line, which enters Penn Station serving Amtrak and MARC's Penn Line to the southeast.

The highway passes underneath the Howard Street and US 1/US 40 Truck (North Avenue) bridges and by the Baltimore Streetcar Museum buildings and sheds.

MD 25 passes under Wyman Park Drive just south of the former Stieff Silver Company factory building and Mount Vernon Mill No.

The highway intersects Cold Spring Lane next to the joint campus of the Baltimore Polytechnic Institute (Baltimore City public high school specializing in math, science, engineering and technology) and the all-girls Western High School and passes between the Village of Cross Keys (an apartment-condo complex with a small shopping center/mall) on the west and the community of Roland Park on the hills above to the east as a four-lane undivided highway.

MD 25 intersects Northern Parkway, (built over and segmented with former Belvedere Avenue) then descends again into the Jones Falls valley and passes through the center of Mount Washington.

The neighborhood contains the North Baltimore Aquatic Club, where American Olympics team member Michael Phelps trained, and an intersection with Kelly Avenue and its Bridge which connects to the west with the hilly community of Mount Washington, where the highway reduces to two lanes.

The state highway ascends from the stream valley and curves northwest between Robert E. Lee Memorial Park (a Baltimore City park located just barely in Baltimore County) with its historic Lake Roland and dam from the old 1860 city waterworks system to the northeast and the Bare Hills House on the southbound side of the highway.

The state highway crosses Blackrock Run again and intersects MD 137 (Mount Carmel Road) at Whitehouse between Hampstead and Hereford.

On the December 27, 1791, the Maryland General Assembly authorized Elisha Tyson, William & Charles Jessop, John Ellicott, George Leggett, Robert Long, Jacob Hart, and John Stricker to lay out a road, not to exceed 40 feet (12 m) wide, from their flour mill-seats on Jones Falls, then in Baltimore County, southerly to Baltimore Town, thereafter known as the Falls Road.

The company was authorized to build and operate a turnpike "for the accommodation of the inhabitants on Jones's Falls, and the country adjacent", running from "the ford by Messieurs [William] Patterson and [John] Stricker's mill" northerly to "the cross roads by the limekiln of Richard Caton" (Brooklandville).

[11] The Falls Turnpike began building the road, but lacked funds to complete it, and another law passed January 15, 1817 allowed the company to increase their capitalization and to charge tolls for travel on the extension.

[12] On March 12, 1828, the General Assembly ordered the company to, within six months, return this extension to the county for use as a free public road, and the turnpike was thus cut back to Brooklandville.

Due to the impossibility of determining how far a customer had traveled, the Baltimore County Court allowed the company to charge a full toll for passing over any part of the road.

[28] Shortly after 1930, work began on a bridge over the Northern Central Railroad, whose right-of-way is now followed by the Baltimore Light RailLink, at Bare Hills; this structure was completed by 1934.

[34][35] With the completion of the Jones Falls Expressway, I-83 became the main highway from the north into downtown Baltimore and MD 25 was relegated to a local thoroughfare.

[35] MD 25 was closed for several months for the replacement of the highway's bridges over the Baltimore Light RailLink and Jones Falls at Bare Hills in 1991 and over I-695 near Brooklandville in 1996.

MD 25A is the designation for the 0.58-mile (0.93 km) portion of the Jones Falls Expressway north of the Baltimore Beltway in Brooklandville.