Background: Physalis alkekengi (PA) is used as a topical medicine in the treatment of tumors. The diuretic, laxative, and anti-inflammatory properties of PA have been studied. Due to the widespread usage of PA, investigation on the plausible side effects is of great concern. Objectives: This study was done to assess the effects of aqueous extract of PA on the heart and aortic tissue of adult BALB/c mice. Methods: Fifty BALB/c mice aged 10-12 weeks, weighing 25 ± 2 g, were divided into five groups of control, sham, and three experimental groups (receiving PA aqueous extract at 7, 15, and 19 g/Kg) for four weeks. Lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) enzymes were measured. Moreover, histological processing and macroscopic investigation were performed. Results: Our data showed that different doses of PA aqueous extract caused a significant increase in aortic diameter compared to the control and sham groups (P-value ≤ 0.05). The macroscopic heart investigation revealed that the experimental groups had more apparent blood vessels than the control group. In microscopic examinations, an increase was observed in the interstitial spaces and unrecognizable stepped lines. The experimental groups demonstrated a significant decrease in the levels of LDH and CPK compared to the control and sham groups (P-value ≤ 0.5). Therefore, PA aqueous extract has adverse impacts on the heart, aorta, and cardiac enzymes, which were more significant at high doses. Conclusions: Our finding showed that PA has destructive impacts on the heart tissue and PA use needs more investigation and attention.