The rankings are based on votes submitted by the magazine's readers for its 16th annual World's Best Awards.
The Umstead is the only North Carolina hotel in the top 50. It was ranked 34th last year.
Umstead is the brainchild of philanthropist and businesswoman Ann Goodnight, SAS founder Jim Goodnight's wife.
It has 150 rooms and suites on a 12-acre site.
For a list of Travel and Leisure's world hotel rankings go here.