The 23-year-old Romero, who has pitched just four games above Double-A in six minor league seasons, will take the mound against the Toronto Blue Jays.
He has pitched 21 innings at Triple-A Rochester, going 0-1 with a 2.57 ERA and 20 strikeouts.
"There's something good about the process of having [prospects] going step-by-step, for most guys," Twins manager Paul Molitor told reporters Monday. "But every once in a while, you get exceptions."
Romero had elbow surgery in July 2014 and missed all of the 2015 season.
Hughes, who went on the DL early in the season with a strained oblique, has struggled, giving up six runs and four walks in seven innings for a 7.71 ERA. He lasted just 3 2/3 innings in his last start -- a 15-9 loss to Cincinnati on Friday.
The Associated Press contributed to this report.