Keith Grace, a mixed-media painter, and his wife, Shari, a graphic artist and stained-glass sculptor, came from Rockford, Ill. Renowned printmaker Kent Ambler and his wife, Peggy, came from Roswell, N.M. And Yuri Tsuzuki, a sculptor and painter, relocated from Bogota, Colombia.

All of these artists—and hundreds of others—have chosen to live in Greenville, S.C., a Southern city of about 68,000 people that once called itself the Textile Capital of the World. Today, the vibrant arts scene is revitalizing the city itself, attracting other artists, young professionals and families wanting a fun, affordable place to live.

“We came looking for artists,” says Mr. Ambler, who is 47. He and his wife wanted to live somewhere warm, but California was too expensive and they didn’t think Florida was a good fit for his artwork. When a teaching job opened, they moved in 2000 to Seneca, S.C., about 30 miles west of Greenville, and bought a 1,800-square-foot studio for $88,000, selling it seven years later for $210,000.

In October 2000, Mr. Ambler began showing his work in a Greenville gallery and started looking for homes nearby. He paid $410,000 for a 4,000-square-foot, four-bedroom, 4½-bath, ranch-style house on 12 acres in 2009 in a neighborhood called Paris Mountain that’s about a five-minute drive from downtown. Built in the 1960s, it was structurally sound but needed slight renovations.

He furnished it with pieces he made in his shop along with Midcentury Modern furniture found on eBay and estate sales and blanketed walls and shelves with art made by friends. This past year Mr. Ambler finished building a new 1,600-square-foot art studio out of what was a garage, spending about $120,000 on it along with $30,000 for the construction of a koi pond and landscaping work.