Hypoxia/reoxygenation (H/R)-induced myocardial cell injury is the main cause of acute myocardial infarction (AMI). Many proofs show that circular RNA plays an important role in the development of AMI. The purpose of this study was to investigate the role of circSAMD4A in H/R-induced myocardial injury. The levels of circular SAMD4A (circSAMD4A) were detected in the heart tissues of AMI mice and H/R-induced H9C2 cells, and the circSAMD4A was suppressed in AMI mice and H/R-induced H9C2 cells to investigate its' function in AMI. The levels of circSAMD4A and miR-138-5p were detected by real-time quantitative PCR, and MTT assay was used to detect cell viability. TUNEL analysis and Annexin V-FITC were used to determine apoptosis. The expression of Bcl-2 and Bax proteins was detected by Western blot. IL-1 beta, TNF-alpha and IL-6 were detected by ELISA kits. The study found that the levels of circSAMD4A were up-regulated after H/R induction and inhibition of circSAMD4A expression would reduce the H/R-induced apoptosis and inflammation. MiR-138-5p was down-regulated in H/R-induced H9C2 cells. circSAMD4A was a targeted regulator of miR-138-5p. CircSAMD4A inhibited the expression of miR-138-5p to promote H/R-induced myocardial cell injury in vitro and vivo. In conclusion, CircSAMD4A can sponge miR-138-5p to promote H/R-induced apoptosis and inflammatory response.