PA 74 begins at the Maryland border in Peach Bottom Township in York County, where the road continues south into that state as MD 165.

PA 74 continues north through a mix of farmland and woodland with some homes, curving to the northwest and crossing the Muddy Creek into Lower Chanceford Township.

The route enters Chanceford Township and passes through the community of Collinsville, where it heads near homes before running past farms and a few businesses.

Here, residential development along the route increases as it continues near more farms with some woods, passing through the community of Petersburg and curving to the west.

The road heads past more homes and a few businesses before it reaches the downtown area of Red Lion and comes to an intersection with PA 24.

PA 74 leaves Red Lion for York Township and gains a center left-turn lane as it passes businesses, turning northwest and becoming East Main Street.

PA 74 heads past businesses and becomes a four-lane divided highway as it passes west of the York County School of Technology, turning northwest and coming to a partial cloverleaf interchange with I-83.

The road enters Spring Garden Township and runs past a mix of residences and commercial establishments, curving to the northwest.

The one-way pair continues through urban residential areas of rowhouses with a few businesses, with West Market Street becoming two-way and two lanes wide.

[2][3] PA 74 fully enters West Manchester Township and becomes a four-lane divided highway, heading past businesses.

The route comes to an intersection with the western terminus of PA 238 before it crosses the Little Conewago Creek into Dover Township and heads west past residential and commercial development in the community of Weigelstown.

Past this intersection, the route becomes North Main Street and passes through more developed areas of the borough before it crosses back into Dover Township.

Farther northwest, the road runs through wooded areas with some homes as it bypasses the community of Mount Royal to the southwest.

[2][3] The route crosses the Conewago Creek into Warrington Township and runs through a mix of farm fields, woods, and residences to the southwest of Gifford Pinchot State Park.

PA 74 leaves Wellsville for Warrington Township again, becoming Carlisle Road and heading west and southwest through farm fields and woods with some homes.

At this point, PA 74 turns northeast for a short concurrency with US 15 on a four-lane divided highway past businesses before it splits north onto two-lane undivided York Road and heads back into Carroll Township.

[2][3] PA 74 enters Monroe Township in Cumberland County and continues west-northwest along York Road through a mix of farmland and woodland with some residences.

The route reaches the community of Brandtsville, where it turns north and crosses Norfolk Southern's Lurgan Branch railroad line and the Yellow Breeches Creek before curving northwest and winding through farmland.

PA 74 continues through farmland with a few homes, crossing the Appalachian Trail, before residential development near the road increases further to the northwest.

PA 74 passes more farms before it enters forested areas and begins to ascend Blue Mountain, turning northwest and then northeast.

The road makes a hairpin turn to the west and crosses into Lower Frankford Township as it reaches the summit of the mountain.

[2][5] PA 74 enters Turbett Township in Juniata County and becomes an unnamed road, turning southwest to ascend Tuscarora Mountain.