[3] Sam Venable's home on the northeast corner of Ponce de Leon Avenue and Oakdale Road was bought in 1959 for $60,000 by the St. John's Lutheran Church.

At the next two intersections, it takes multiple numbered routes from North Avenue, which runs one block to the south and forms the boundary between Midtown and downtown Atlanta.

Passing Piedmont Avenue and the Edward C. Peters House, Ponce forms the border of NRHP-listed Historic Midtown to the north and Old Fourth Ward to the south.

Ponce de Leon Avenue then passes under a former rail bridge which is part of the BeltLine trail, after which it forms the border between the Poncey-Highland neighborhood to the south and Virginia-Highland to the north.

[6] A few blocks further east is the intersection with North Highland Avenue (from which the name of Poncey-Highland is derived), and at this intersection are found the historic Plaza Theatre and Briarcliff Hotel, designed by the same architect as Atlanta City Hall and once home to Coca-Cola heir Asa G. Candler Jr. Druid Hills Presbyterian Church, despite the name, is also located in this area, across the street from Briarcliff Plaza.

Although still within Atlanta city limits, it also crosses the county line from Fulton into DeKalb at this street and enters the Druid Hills neighborhood.

After a northward curve, it loses its other four route numbers at a split with Scott Boulevard, and continues eastward into the city of Decatur as West Ponce de Leon Avenue.

The only way to access I-285 south is to exit onto Church Street, since this is a split diamond interchange, and the two roads run parallel to each other separated by a railroad line.

[9] As of April 2011[update], the Georgia Department of Transportation has decided to begin the design of safety improvements for pedestrians on the two-mile stretch of Ponce between Piedmont and N. Highland/Moreland.