PA 45 begins at an intersection with PA 453 and the western terminus of PA 45 Truck in Morris Township, Huntingdon County, heading northeast on two-lane undivided Spruce Creek Road. The road passes through farmland with some homes a short distance to the west of Short Mountain. The route crosses into Spruce Creek Township and heads into forested areas, curving northwest to run parallel to Norfolk Southern's Pittsburgh Line and the Little Juniata River which are both located northeast of the road. PA 45 turns northeast and comes to a one-lane underpass that carries the route under Norfolk Southern's Pittsburgh Line before it turns southeast and runs between the river to the northeast and the railroad tracks to the southwest as a two-lane road. The route turns east and crosses the Little Juniata River, at which point it passes homes and some businesses in the community of Spruce Creek. The road winds north through wooded areas, with Spruce Creek parallel to the east. PA 45 curves northeast and heads through a mix of farmland and woodland with some homes parallel to the creek, with Rothrock State Forest and Tussey Mountain located a short distance to the southeast. The route heads into Franklin Township and passes through an S-curve to the north before it heads northeast to the community of Colerain Forge. The road turns east and then northeast, continuing through rural land and passing through the community of Franklinville. PA 45 heads through farmland and comes to an intersection with the southern terminus of PA 350 and the eastern terminus of PA 45 Truck in the community of Seven Stars. Past this intersection, the route heads northeast through an agricultural valley between The Barrens to the northwest and Tussey Mountain to the southeast. Farther northeast, the road passes through the communities of Graysville and Pennsylvania Furnace.