Spruce Run is a tributary of Buffalo Creek in Union County, Pennsylvania, in the United States.

Spruce Run begins in a narrow valley in eastern Hartley Township.

It flows east-northeast for a few miles, heading along the northern side of Sand Mountain and entering Lewis Township.

Several tenths of a mile after this, it turns southeast and receives Muddy Run, its second and final named tributary, from the right.

A few tenths of a mile further downstream, the stream reaches its confluence with Buffalo Creek.

[1] Spruce Run joins Buffalo Creek 7.70 miles (12.39 km) upstream of its mouth.

[1] Jökulhlaup surfaces and former ice-dammed lakes exist in the vicinity of Spruce Run.

[9] The main stem of the stream makes up 13 percent of the Buffalo Creek drainage basin.

[8] Spruce Run was entered into the Geographic Names Information System on August 2, 1979.

[5] The stream has had its name since at least June 11, 1769, when Colonel Kelly filed an application for land nearby.

[12] Barney Parsons, one of the early settlers in the area, had reached Spruce Run by the fall of 1769.

[7] In around 1900, the Kulp Lumber Mill at Linntown processed millions of board feet of timber from the stream's watershed.

[13] The Sugar Valley Railroad was incorporated on October 19, 1900 and part of it was located at Running Gap, near the stream.

[14] A concrete tee beam bridge carrying State Route 1001 was built over Spruce Run in 1921 and repaired in 1947.

[15] From its source to the eastern boundary of Bald Eagle State Forest, the drainage basin of Spruce Run is designated as Exceptional Value and a Migratory Fishery.

[16] Wild trout naturally reproduce in the stream from its headwaters downstream to the tributary Black Run, a distance of 12.24 miles (19.70 km).

[8] A reach of Spruce Run with a length of 6.5 miles (10.5 km) was stocked with fish in the past.