Two sets of older lady friends. One in Columbus, two in South Florida, one in Louisville. Looking for easily accesss via plane, scenery, good food, and relaxed atmosphere.

I have been to Ashville, Charleston, Savanah, Nashville. But would be up for a second visit.

What would you suggest. Any rental suggestions?

Wilmington, NC is an antebellum Old South town which has the largest historic district in North Carolina with many buildings dating from 1840. It is an authentic Southern town with good beaches and water and waves. Can be hot and humid in summer.

Beach house? Wilmington has Wrightsville Beach also which is an old style beach
Pawley's Island Beach. This is as old school as you can get--no commercial development on the island. And is an historic site for the houses where the rice planters from Charleston spent the summer to escape the malarial mosquitoes. Our kids did a nice VRBO house there. You could do a day trip to Charleston easily. Food, of course, is sublime. There are things to do nearby--Brookgreen Gardens has a wonderful art and sculpture collection. It was the summer home of the Huntingtons and Anna Huntingon did massive metal sculptures. Atalanta, their home is also tourable and is interesting for it's Moorish architecture. Hobcaw Barony is a historic site and now a Clemson ecology area. Reservation required to do a tour. And there is a nature preserve --Tom Yawkey preserve--for nature. Also reservations required. For other rentals in Pawley's there is Litchfield.
Oh, and Georgetown is nearby (20 minutes)--an absolutely charming town dating from the Revolutionary War with wonderful old homes and live oaks. Great waterfront area )on the river) with shops and restaurants.
When do you sant to do this? Fly into Myrtle Beach--easy small airport. 40 minutes to Pawley's

Wilmington would be a fine choice but I'd prefer Gretchen's suggestion of Pawley's Island. Ticks all of your boxes. Plus Charleston nearby.

How about Santa Fe?

Santa Fe would be a good choice though not exactly close to where they live. For many Santa Fe is magical place since it's an ancient Spanish Colonial town with an historic plaza containing the Palace of the Governors (1610) and the nearby oldest house (1646) and church (1610) in America. The narrow streets are lined with adobe home. It has many cultures including that of those descended from the original Spanish colonists, Native American, New Age, artistic, and more. Some think it is an Adobe Theme Park because of its excessive tourism and millionaires. It is located on the treeless high desert.

Have you ever considered New Orleans? Downtown ( French Quarter) has mostly been restored since Katrina. There are a few good places to stay in the Garden District near the St. Charles St. trolley line.