Heart failure (HF) is a major health issue, affecting up to 2% of the adult population worldwide. Given the increasing prevalence of obesity and its association with various cardiovascular diseases, understanding its role in HFrEF outcomes is crucial. This study aimed to investigate the impact of obesity on in-hospital mortality and prolonged hospital stay in patients with heart failure with reduced ejection fraction (HFrEF). We conducted a retrospective analysis of 425 patients admitted to the cardiology unit at the University Clinical Hospital in Wroclaw, Poland, between August 2018 and August 2020. Statistical analyses were performed to evaluate the interactions between BMI, sex, and comorbidities on in-hospital mortality. Significant interactions were found between sex and BMI as well as between BMI and post-stroke status, affecting in-hospital mortality. Specifically, increased BMI was associated with decreased odds of in-hospital mortality in males (OR = 0.72, 95% CI: 0.55–0.94, p < 0.05) but higher odds in females (OR = 1.18, 95% CI: 0.98–1.42, p = 0.08). For patients without a history of stroke, increased BMI reduced mortality odds (HR = 0.78, 95% CI: 0.64–0.95, p < 0.01), whereas the effect was less pronounced in those with a history of stroke (HR = 0.89, 95% CI: 0.76–1.04, p = 0.12). In conclusion, the odds of in-hospital mortality decreased significantly with each 10% increase in BMI for males, whereas for females, a higher BMI was associated with increased odds of death. Additionally, BMI reduced in-hospital mortality odds more in patients without a history of cerebral stroke (CS) compared to those with a history of CS. These findings should be interpreted with caution due to the low number of observed outcomes and potential interactions with BMI and sex.