Identifying clinical predictive factors related to the prognosis of septic patients with heart failure is crucial for guiding their treatment. The present study explored prognostic factors in septic patients with heart failure using retrospective data from the Medical Information Mart for Intensive Care IV database. Among 567 septic patients with heart failure included, 166 died, and 401 exhibited survival at 28 days. Univariate analysis showed that in the 28-day mortality group, age, white blood cell count, total bilirubin, blood urea nitrogen, serum creatinine, lactate, 72-hour overall fluid balance, 72-hour total dosage of norepinephrine, and 72-hour serum potassium variability were significantly higher (all P < .05), while body mass index, pH value, and arterial partial pressure of oxygen were significantly lower (all P < .05). Binary logistic regression analysis identified age [ OR = 1.054 (1.032–1.078)], total bilirubin [ OR = 1.169 (1.016–1.346)], and 72-hour serum potassium variability [ OR = 1.617 (1.456–1.794)] as independent predictors of 28-day mortality (all P < .05). Internal validation with ROC analysis in a total of 245 patients showed that the combination of the 3 indicators yielded a higher AUROC value [0.888 (0.841–0.924)] than that of any single indicator [age: AUROC = 0.637 (0.574–0.698); total bilirubin: AUROC = 0.548 (0.484–0.612); 72-hour serum potassium variability: AUROC = 0.868 (0.819–0.908)], indicating good predictive performance. These findings suggest that 72-hour serum potassium variability, age, and total bilirubin are independent risk factors for 28-day mortality in septic patients with heart failure, and their combination significantly enhances prognostic prediction.