Alcohol remains the most frequently used intoxicant, posing a significant global health concern. Binge drinking has been linked to acute cardiovascular complications, including reduced cardiac performance, arrhythmias, and blood pressure instability. Additionally, there is a growing number of clinical reports describing severe adverse cardiac events associated with the recreational use of synthetic cannabinoids. Recent surveys reveal a troubling rise in polydrug misuse, particularly among young adults, with an increasing number of cases linked to fatal outcomes. This study aimed to characterize left ventricular performance in mice following combined acute alcohol and synthetic cannabinoid exposure using complex hemodynamic measurements via the pressure-volume (P-V) approach. Our findings revealed that alcohol ingestion or intravenous synthetic cannabinoid (CP55,940) administration led to a dose-dependent decline in systolic cardiac performance in mice. Moreover, the concurrent administration of alcohol and CP55,940 led to cardiodepression, surpassing the contractile dysfunction observed with each drug administered individually. Intravenous administration of the cannabinoid type-1 receptor (CB1R) antagonist rimonabant largely improved the combined drug administration-induced left ventricular contractile dysfunction in mice, while its intracerebroventricular administration resulted in only partial restoration of normal cardiac function, implicating a role for both central and peripheral CB1R signaling. Our results emphasize the severe cardiac consequences of simultaneous alcohol and synthetic cannabinoid misuse and offer a potential therapeutic avenue for mitigating the adverse cardiac effects of their combined use by repurposing CB1R antagonists.