OBJECTIVE: To explore the correlation between Blood Routine Indicators (BRI) and sepsis using machine learning algorithms (MLAs) and evaluate their application in early sepsis for prognosis assessment. METHODS: A total of 4,558 blood routine data (BRD) samples were collected, including 149 sepsis patients and 186 patients with common infections (CI). A binary logistic regression model (BLRM) was constructed to predict sepsis based on BRI. Additionally, MLAs were applied, including support vector machines, neural networks, Bayesian classifiers, k-nearest neighbors), decision trees, and random forest classification models (RFCM). The performance of these seven predictive models was evaluated. RESULTS: The RFCM demonstrated the best predictive performance among the MLAs, with accuracy of 86.97%, precision of 87.02%, recall of 86.97%, and F1 score of 0.87. These metrics were significantly higher than those of the BLRM (accuracy: 68.77%, precision PRE: 71.45%, recall: 69.47%, F1 Score: 0.70). In the random forest model, red blood cell volume distribution width (RDW) was identified as the most significant feature, with RDW-coefficient of variation contributing 6.98% and RDW-standard deviation contributing 5.32%. CONCLUSION: Combining blood routine indicators (BRI) with MLA has considerable potential in predicting sepsis. The RFCM showed the highest predictive value, and RDW may play a crucial role in sepsis prediction.