Wise Blood is set in the American South shortly after World War II, and most of the action takes place in the fictional town of Taulkinham, Tennessee. It seems like the action of the book spans a few months, but it could be longer.
Although several of the towns that are referenced in the novel are fictional—including Taulkinham, Eastrod, Melsy, and Stockwell—the novel also references real places like Chicago. Through this mixture of real and fictional place names, O'Connor makes the novel about the South without making it about a specific town or city.
The characters express religious, political, and social views that capture the novel's time and place. For example, when the street vendor gets mad at Asa and Sabbath Hawks for taking the crowd's attention away from him, he yells "These goddman Communist foreigners!" O'Connor wrote the novel in the late 1940s and early 1950s, which corresponds with the McCarthy era and the Second Red Scare.
Other characters reveal similar kinds of skepticism, such as when Hazel tells Mrs. Flood he belongs to the "Church Without Christ" and Mrs. Flood looks at him suspiciously and asks whether it's Protestant "or something foreign." Implicitly, she's suggesting that Catholicism is a foreign religion. In the South, most Christians belong to Protestant sects. A common sect in Tennessee is the Church of Christ, which seems to be what Hazel references when he comes up with the Church Without Christ. Although O'Connor grew up in south Georgia, her family was Catholic, so this comical exchange captures a perspective she likely encountered often.
In two instances, O'Connor inscribes religious messages into the setting itself. Both of these signs seem to taunt Hazel. He comes across the first of these in the fourth chapter, when he drives by a boulder with white writing on it: "WOE TO THE BLASPHEMER AND WHOREMONGER! WILL HELL SWALLOW YOU UP?" Underneath this menacing message is a somewhat more peaceful one: "Jesus Saves." Hazel comes across the next sign in the thirteenth chapter, just before the highway patrolman pulls him over. Although the narrator notes that he saw it and "intentionally did not read" it, Hazel again seems bothered by the sign: "Jesus Died for YOU." Through these signs, O'Connor makes the novel's religious theme a physical part of the setting.