Aims Heart failure with reduced ejection fraction (HFrEF) poses significant challenges for clinicians and researchers, owing to its multifaceted aetiology and complex treatment regimens. In light of this, artificial intelligence methods offer an innovative approach to identifying relationships within complex clinical datasets. Our study aims to explore the potential for machine learning algorithms to provide deeper insights into datasets of HFrEF patients. Methods To this end, we analysed a cohort of 386 HFrEF patients who had been initiated on sodium‐glucose co‐transporter‐2 inhibitor treatment and had completed a minimum of a 6‐month follow‐up. Results In traditional frequentist statistical analyses, patients receiving the highest doses of beta‐blockers (BBs) (chi‐square test, P = .036) and those newly initiated on sacubitril‐valsartan (chi‐square test, P = .023) showed better outcomes. However, none of these pharmacological features stood out as independent predictors of improved outcomes in the Cox proportional hazards model. In contrast, when employing eXtreme Gradient Boosting (XGBoost) algorithms in conjunction with the data using Shapley additive explanations (SHAP), we identified several models with significant predictive power. The XGBoost algorithm inherently accommodates non‐linear distribution, multicollinearity and confounding. Within this framework, pharmacological categories like ‘newly initiated treatment with sacubitril/valsartan’ and ‘BB dose escalation’ emerged as strong predictors of long‐term outcomes. Conclusions In this manuscript, we not only emphasize the strengths of this machine learning approach but also discuss its potential limitations and the risk of identifying statistically significant yet clinically irrelevant predictors.