Obesity is a risk factor for heart disease. Persistent exposure to excess lipids in the circulation can harm the heart by accumulating hazardous metabolic by-products such as reactive oxygen species and ceramides, which can cause myocyte malfunction and death by activating signaling pathways. Herbs are one of the most popular weight-loss alternative medicines in the world. Our study aimed to evaluate the possible effects of celery seed oil against high-fat diet-induced lipotoxicity of heart in rats. The study was conducted on 40 male Wistar rats that were classified into 2 groups. Group I (GpI) served as control. GpII was obese rats, subdivided into four subgroups (untreated, treated with orlistat drug, celery seed oil, and a combination of celery seed oil /orlistat drug. At the end of treatment, all rats were scarified, blood samples and heart tissues of the rats were collected. Celery seed oil showed ameliorative effect against high-fat diet-induced lipotoxic heart disease through multiple interrelated mechanisms including alleviation the histological changes, boosting the antioxidant status, improving lipid profile, and reducing fatty acid accumulation in cardiac tissue. The treatment with a combination of celery seed oil /orlistat drug showed the best effect. In conclusion, celery seed oil could be used for the protection against obesity alone or used as adjuvant with orlistat drugs to enhance their pharmacological effect against lipotoxic heart disease.