Diabetes mellitus (DM) might increase the incidence and mortality of cardiac failure after acute myocardial infarction (AMI) in patients. We attempted to investigate whether Caveolin-3 showed beneficial effects in DM patient post-MI injury through the cAMP/PKA and BDNF/TrkB signaling pathways. The activity of ADRB2 and cAMP/PKA signaling were impaired in nondiabetic ischemia-reperfusion (I/R) group compared with the sham and DM groups and were more impaired in diabetic I/R group than in the I/R group. In H9C2 cells, high-glucose (HG) stimulation further enhanced H/R injury by promoting cell apoptosis, inhibiting cell viability, and suppressing TrkB and Akt signaling; in contrast, the ADRB2 agonist isoprenaline (ISO) significantly attenuated the above-described effects of HG stimulation. Caveolin-3 overexpression promoted the localization of ADRB2 on the membrane of the HG-stimulated H9C2 cells, subsequently inhibiting apoptosis and promoting cell viability. Under HG stimulation, Caveolin-3 overexpression enhanced the activity of the cAMP/PKA and BDNF/TrkB signaling pathways, whereas ADRB2 silencing reversed the effects of Caveolin-3 overexpression. In conclusion, ADRB2 agonist promoted the activity of the BDNF/TrkB and cAMP/PKA signaling pathways, mitigating the HG-aggravated H/R injuries in H9C2 cells. Caveolin-3 exerts a protective effect on diabetic hearts against I/R damage through the β2AR, cAMP/PKA, and BDNF/TrkB signaling pathways.