SR 28 begins northeast of Wenatchee at an intersection with Eastmont Avenue and the concurrent US 2 and US 97 at the east end of the Richard Odabashian Bridge.

The highway travels south through the rural–exurban portion of unincorporated Douglas County and enters East Wenatchee, where it turns southeasterly to follow the Columbia River and the Apple Capital Recreation Loop Trail.

[6] SR 28 passes Pangborn Memorial Airport and the town of Rock Island, where it joins a section of the BNSF Railway's Columbia River Subdivision.

[7][8] The highway turns south near the Rock Island Dam, following the river as it winds around Badger Mountain and the Beezley Hills, passing some scattered vineyards and orchards in the canyon.

[9] Near Trinidad, SR 28 turns east and leaves the river and railroad, entering Grant County and ascending from Lynch Coulee.

[4][6] The highway leaves Quincy and turns northeast at an intersection with SR 283, crossing under and following the railroad into Ephrata, located on the east edge of the Beezley Hills.

The highway continues northeast from Harrington through rolling terrain and makes a gradual turn to the north, leaving the railroad to follow a section of Bluestem Creek as it approaches Davenport.

[24][25] The Wenatchee–Quincy highway was fully completed in 1926, using $200,000 in state appropriations (equivalent to $2.76 million in 2023 dollars)[26] and replacing an earlier road-and-ferry on the west side of the river.

[34][35] In the early 1960s, business groups in Grant County had unsuccessfully sought to move US 2 or a designated alternate route to the corridor that would later become SR 28.

[38] In the 1980s and 1990s, government officials in East Wenatchee proposed the construction of a parkway along the Columbia River to replace a section of SR 28 with a wider, modern highway.

[45] A long-term plan adopted in 2006 proposed widening the East Wenatchee section of the highway to four lanes by 2025 to meet projected demand from a larger regional population.