Abstarct: Aim:The aim of the present study was to modulate the changes induced by marijuana administration and to examine the effects of crocin and berberine hydrochloride supplementation along with aerobic exercise on histopathological changes in the liver tissue of female Wistar rats. Methodology: The statistical population of the study consisted of 60 adult female Wistar rats weighing between 140 and 160 grams. A total of 56 rats were randomly divided into seven groups (n = 8 per group): 1) Control, 2) Marijuana, 3) Marijuana + Aerobic Exercise, 4) Marijuana + Berberine Hydrochloride, 5) Marijuana + Crocin, 6) Marijuana + Aerobic Exercise + Crocin, and 7) Marijuana + Aerobic Exercise + Berberine Hydrochloride. Marijuana was administered intraperitoneally at a dose of 5 mg/kg body weight in five injections at 24-hour intervals. The exercise groups performed aerobic training for four weeks, running at a speed of 25 m/min for 30 minutes per day, six days a week (a total of 24 sessions). The supplement groups received crocin (40 mg/kg body weight) and berberine hydrochloride (100 mg/kg body weight) six days per week for four weeks. Twelve hours after the final exercise and supplementation session, the rats were deeply anesthetized with xylazine (5 mg/kg) and ketamine (50 mg/kg). After complete anesthesia, the rats were dissected by trained personnel, and liver tissue samples were collected for analysis of dependent variables. Hematoxylin and eosin (H&E) staining was performed to observe structural changes, while Masson’s trichrome staining was used to assess hepatic fibrosis. Inflammatory cell count and necrosis were evaluated using a light microscope. To determine significant differences among the groups, the nonparametric Kruskal–Wallis test was employed, and pairwise comparisons were conducted using post-hoc tests. Results:The results indicated that marijuana consumption caused undesirable histological changes in the liver, including hepatocyte damage, central lobular vein dilation, portal area inflammation, and sinusoidal space disruption. The combination of marijuana with aerobic exercise and supplements of berberine and crocin significantly reduced these damages. Notably, the marijuana + aerobic exercise + berberine group showed the greatest improvement in liver histology, indicating a stronger protective effect of berberine compared to crocin. Conclusion: The findings of this study suggest that marijuana exerts a significant destructive effect on the liver by inducing inflammation, necrosis, and severe structural changes. Exercise interventions effectively protected liver tissue, while the protective effect of crocin was less pronounced compared to berberine. These results highlight the need for further investigations in future studies.