Purpose: Machine Learning (ML) is rapidly growing in capability and is increasingly applied to model outcomes and complications in medicine. Surgical site infections (SSI) are a common post-operative complication in spinal surgery. This study aimed to develop and validate supervised ML algorithms for predicting the risk of SSI following minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF). Methods: This single-central retrospective study included a total of 705 cases between May 2012 and October 2019. Data of patients who underwent MIS-TLIF was extracted by the electronic medical record system. The patient’s clinical characteristics, surgery-related parameters, and routine laboratory tests were collected. Stepwise logistic regression analyses were used to screen and identify potential predictors for SSI. Then, these factors were imported into six ML algorithms, including k-Nearest Neighbor (KNN), Decision Tree (DT), Support Vector Machine (SVM), Random Forest (RF), Multi-Layer Perceptron (MLP), and Naïve Bayes (NB), to develop a prediction model for predicting the risk of SSI following MIS-TLIF under Quadrant channel. During the training process, 10-fold cross-validation was used for validation. Indices like the area under the receiver operating characteristic (AUC), sensitivity, specificity, and accuracy (ACC) were reported to test the performance of ML models. Results: Among the 705 patients, SSI occurred in 33 patients (4.68%). The stepwise logistic regression analyses showed that pre-operative glycated hemoglobin A1c (HbA1c), estimated blood loss (EBL), pre-operative albumin, body mass index (BMI), and age were potential predictors of SSI. In predicting SSI, six ML models posted an average AUC of 0.60-0.80 and an ACC of 0.80-0.95, with the NB model standing out, registering an average AUC and an ACC of 0.78 and 0.90. Then, the feature importance of the NB model was reported. Conclusions: ML algorithms are impressive tools in clinical decision-making, which can achieve satisfactory prediction of SSI with the NB model performing the best. The NB model may help access the risk of SSI following MIS-TLIF and facilitate clinical decision-making. However, future external validation is needed.