The 18-year-old tournament wildcard won 83 percent of her first serve points, more than double that of the 20th-seeded Spaniard, and converted five of her seven break-point opportunities in the 52-minute blow out.
Andreescu smashed a forehand winner on match point to seal the win and smiled before shaking the hand of the 2016 French Open and 2017 Wimbledon champion.
She said the key was not being intimidated and playing her game, which features ferocious groundstrokes, well-timed drop shots and an abundance of speed.
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"I just went out there and went for it," she told reporters after the match.
"I didn't focus on who was on the other side. It really helped me. I stuck to my tactics, which was to put pressure on her forehand, move her around, change rhythm like I always do, play my game."
Andreescu has grown familiar with victory of late with Wednesday's success her 26th win of the year, the most of any WTA player.
Next up for the world number 60 is a meeting with sixth-seeded Elina Svitolina, a 4-6 6-4 6-4 winner over 19-year-old Marketa Vondrousova.
Andreescu out of Madrid Open after positive COVID-19 test
WTA Charleston, SC
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