Objective To explore the value of quick Sequential Organ Failure Assessment (qSOFA) score and blood markers in differentiating and predicting emergency heat stroke from sepsis, and to construct a rapid differentiation model. Methods A retrospective cohort study was conducted, including heat stroke patients and sepsis patients admitted to the Chongqing Emergency Medical Center between January 2021 and December 2024. The qSOFA score and blood marker indicators at admission were collected, with the “final diagnosis (sepsis or heat stroke) within 48 hours after admission” as the study endpoint. The logistic regression analysis method was selected to screen for independent predictive factors, construct a joint prediction model, and evaluate the discriminant efficacy using the area under the curve (AUC) of the receiver operating characteristic. Results A total of 133 sepsis patients and 66 heat stroke patients were included. The qSOFA score showed differentiation ability in univariate analysis (P=0.002), but had no independent predictive value after adjusting for diabetes, age, and gender (P=0.565). The results of multiple logistic regression analysis showed that procalcitonin (PCT), C-reactive protein (CRP), and monocyte count (MONO) were independent predictive factors (P<0.05). The combined prediction model of PCT, CRP, and MONO (AUC=0.984) showed higher discriminatory efficacy than PCT (AUC=0.809), CRP (AUC=0.886), and MONO (AUC=0.671). Conclusions The prediction model constructed by combining PCT, CRP, and MONO has good efficiency in differentiating sepsis from heat stroke, providing a reliable clinical decision-making tool for early accurate differentiation in the emergency department.