MLB said in a statement that Santana, 28, was positive for Boldenone, a performance enhancer.
Santana, a right-handed reliever, missed the 2019 season because of Tommy John surgery.
In 2018, he appeared in 69 games for the Pirates, going 3-4 with a 3.31 ERA. He struck out 74 in 66⅓ innings that season.
"The Pirates are disappointed to learn of today's news that Edgar Santana has received an 80-game suspension as a result of a violation of Major League Baseball's Joint Drug Prevention and Treatment Program," Pirates GM Ben Cherington said in a statement. "Because of the confidentiality requirements of the Program, we will not have further comment on this matter."