A large body of literature has identified that circular RNAs play critical roles in regulating the occurrence and development of cardiovascular disease. In the present study, we intended to provide new ideas and perspectives on the functional role of circ‐CBFB in hypoxia/reoxygenation (H/R)‐injured cardiomyocytes. We observed that circ‐CBFB expression was enhanced which was accompanied by a miR‐495‐3p reduction in response to H/R exposure. Functionally, deletion of circ‐CBFB obviously potentiated cell viability and restrained cell apoptosis, which was accompanied by a remarkable elevation of antiapoptotic Bcl‐2 but the repression of proapoptotic Bax and cleaved caspase‐3 in response to H/R. Additionally, the absence of circ‐CBFB dramatically prohibited H/R‐evoked cardiomyocyte oxidative stress, as revealed by a decrease in reactive oxygen species overproduction, diminution in MAD content, and enhancement in SOD, CAT, and GSH‐Px activities. Moreover, elimination of circ‐CBFB resulted in improvement of mitochondrial dysfunction, as assessed by mitochondrial membrane potential, adenosine triphosphate production, and the release of cyto‐c. Interestingly, circ‐CBFB inversely regulated miR‐495‐3p expression via acting as a competing endogenous RNA. VDAC1 was identified to be a functional target of miR‐495‐3p and positively modulated by circ‐CBFB. Mechanically, dissipation of miR‐495‐3p or augmentation of VDAC1 manifestly counteracted the beneficial effects of circ‐CBFB knockdown on H/R‐elicited cardiomyocyte insult. Collectively, these observations demonstrated that absence of circ‐CBFB offered cardio‐protection against H/R‐triggered cardiomyocyte injury by relieving apoptosis, oxidative stress, and mitochondria dysfunction through miR‐495‐3p/VDAC1 axis. This work unveiled an innovative axis of circ‐CBFB/miR‐495‐3p/VDAC1 in H/R‐challenged cardiomyocyte damage, exerting its potential in providing new thoughts in acute myocardial infarction management.