From 1928 to 1935, this designation followed the US 202 corridor when the US Highway System was first signed. In 1935, this route replaced the PA 42 designation from Oxford to Reading and US 120 from there to Sunbury. The only city it traversed was Reading, which it did on Morgantown Road, Lancaster Avenue, Bingaman Street, Fifth Street, and Centre Avenue.
Even though it was only around for half of the 1930s, that short amount of time saw a lot of work take place on its new alignment. In 1938, a new alignment was opened southwest of the Borough of Orwigsburg. Prior to that year, the designation passed through Orwigsburg on Brick Hill Road and Market Street. Also, widening took place from Berkley to Mohrsville, Perry Township line to Hamburg, Briar Road to Pottsville, and Darkwater to Frackville. In 1939, the route was widened in the multiplexed section with US 30.
Upgrading continued into the 1940s with sections from Reading to Berkley and the eastern border of the City of Shamokin to Uniontown in the first year of the decade. In 1941, it was widened from Bohrmans Mill to Briar Road, in Ashland, and between Kulpmont and Ranshaw. In 1946, the route was widened from Port Clinton to Brick Hill Road, Saint Clair to Darkwater, Frackville to Fountain Springs, Centralia to Kulpmont, Ranshaw to Shamokin, and Plum Creek Road to the Rockefeller Township line. In 1947, widening took place from Mohrsville to the Windsor Township line, Ashland to Centralia, and Sunny Side to Snufftown. In the last year of the 1940s, widening took place between Fountain Springs and Ashland.
The 1950s also saw improvements take place, but not to the extent of the 1930s and 1940s. The biggest change was when the route was moved onto the newly constructed Pottsville Boulevard from Mauch Chunk Street to Mill Creek Avenue in Pottsville in 1950. Prior to this, the route followed Center Street and Nichols Street. The remainder of the boulevard, known today as Claude A. Lord Boulevard, from Mount Carbon to Mauch Chunk Street opened and the designation moved. Two major events occurred in 1956: the southern terminus was moved from Oxford to Morgantown and a new alignment west of Hamburg opened. Originally, the route entered the borough on Fourth Street and left on Port Clinton Avenue. A lot of construction to install medians occurred in 1958 with sections from Leesport to the Windsor Township line, Molino to Deer Lake, Brick Hill Road, Bohrmans Hill, Schuylkill Haven to Saint Clair, Ashland to the Northumberland County line, and Weight Scales to Paxinos.
The final decade of US 122's existence saw one last improvement take place. In 1962, the route was divided Ontelaunee to Leesport. Finally in 1963, the US 122 shields came down and replaced with PA 10 from Morgantown to Reading and PA 61 from Reading to Sunbury.