SR 159 was original signed in 1923, on much of its current alignment.[2][3] In 1927 the route was extended south to US 23, along the alignment of former State Route 27.[4][5] The first section of road paved was in 1933 and it was a section from the southern terminus to Meade.[6][7] In 1935 the second section was paved between Meade and Tarlton.[8][9] The final section of the roadway was paved between Tarlton and the northern terminus, in 1938.[10][11] The route was extended north to its current terminus along the former alignment of U.S. Route 22, in 1971.[12][13] In 1972 the highway was extended south to its current terminus along the former alignment of U.S. Route 23.[13][14]
A construction project in Ross County added two roundabouts at a new intersection with SR 207 and the intersection of SR 180. Construction began in October 2019 and was completed the following October.[15][16][17]