Acute coronary syndrome (ACS) represents an important clinical manifestation of coronary artery disease (CAD) and is characterized by a particularly poor prognosis. Myocardial reperfusion through primary percutaneous coronary intervention (PPCI) is imperative in the event of acute ST elevation myocardial infarction (STEMI). Interleukin-22 (IL-22) regulates immune and inflammatory responses. This interleukin has been described in the scenario of the CAD, but there are no data in patients with STEMI undergoing PPCI. Objectives: The goals of this study were to investigate the differences in circulating IL-22 levels between patients with STEMI undergoing PPCI and healthy controls and to determine whether these differences were associated with the culprit coronary artery, door-to-balloon time (DBT), final angiographic result, CAD classification, and presence of diabetes mellitus (DM). Methods: A total of 280 participants were recruited, comprising 210 STEMI cases and 70 healthy controls. Participants underwent clinical and angiographic evaluations, and serum IL-22 levels were measured using an enzyme-linked immunosorbent assay (ELISA). Data analysis was performed using the Mann-Whitney and Fisher tests, with p < 0.05 indicating significance. Results: Serum IL-22 levels were lower in cases (149.63, 84.99-294.56) than in the controls (482.67, 344.33-641.00); p < 0.001. Lower IL-22 levels were associated with the right coronary artery (RCA) (144.57, 70.84-242.43; 146.00, 63.60-279.67; 191.71, 121.80-388.97); p = 0.033. IL-22 was lower with shorter DBT (≤60 min, 106.00, 49.60-171.71; >60 min, 153.00, 88.86-313.60); p = 0.043. Conclusions: IL-22 levels were significantly lower in patients with STEMI than in healthy controls.