The resistance variant faults (RVFs) observed in the mine ventilation system can utterly restrict mine safety production. Herein, a machine learning model, which is based on multi-label k-nearest neighbor (ML-KNN), is proposed to solve the problem of the rapid and accurate diagnosis of the RVFs that occur at multiple locations within the mine ventilation system. The air volume that passes through all the branches of the ventilation network, including the residual branches, was used as the diagnostic model input after the occurrence of multiple faults, whereas the label vector of the fault locations was used as the model’s output. In total, seven evaluation indicators and 1800 groups of randomly simulated faults at the typical locations in a production mine with 153 nodes and 223 branches were considered to evaluate the feasibility of the proposed model to solve for multiple fault locations diagnostic and verify the model’s generalization ability. After ten-fold cross-validation of the training sets containing 1600 groups of fault instances, the diagnostic accuracy of the model tested with the air volume of all 223 branches and the 71 residual branches’ air volume as input was 73.6% and 72.3%, respectively. On the other hand, To further evaluate the diagnostic performance of the model, 200 groups of the multiple fault instances that were not included in the training were tested. The accuracy of the fault location diagnosis was 76.5% and 73.5%, and the diagnostic time was 9.9s and 12.16s for the multiple faults instances with all 223 branches’ air volume and the 71 residual branches’ air volume as observation characteristics, respectively. The data show that the machine learning model based on ML-KNN shows good performance in the problem of resistance variant multiple fault locations diagnoses of the mine ventilation system, the multiple fault locations diagnoses can be carried out with all the branches’ air volume or the residual branches’ air volume as the input of the model, the diagnostic average accuracy is higher than 70%, and the average diagnosis time is less than one minute. Hence, the proposed model’s diagnostic accuracy and speed can meet the engineering requirements for the diagnosis of multiple fault locations for a real ventilation system in the field, and this model can effectively replace personnel to discover ventilation system failures, and also lays a good foundation for the construction of intelligent ventilation systems.