Background: Detection of Lisfranc malalignment leading to the instability of the joint, particularly in subtle cases, has been a concern for foot and ankle care providers. X-ray radiographs are the mainstay in the diagnosis of these injuries; thus, improving the performance of clinicians in interpreting radiographs can noticeably affect the quality of health care in these patients. Here we assessed the performance of deep learning algorithms on weightbearing radiographs for detection of Lisfranc joint malalignment in patients with Lisfranc instability. Methods: In a retrospective study, 640 patients with Lisfranc malalignment leading to instability were recruited plus 640 individuals with uninjured feet and healthy Lisfranc joint as the control group. All radiographs were screened by orthopaedic surgeons. Two deep learning models were trained, validated, and tested (in a ratio 80:10:10) using a single-view (anteroposterior) and 3-view (anteroposterior, lateral, oblique) radiographs. The performances of the models were reported as sensitivity, specificity, positive and negative predictive values, accuracy, F score, and area under the curve (AUC). Results: No significant differences were observed between the patients and the controls regarding age, gender, race, and body mass index. The best deep learning algorithm outperformed our human interpreters (<1% vs ~10% misdiagnosis), 94.8% sensitivity, 96.9% specificity, 98.6% accuracy, 95.8% F score, and 99.4% AUC. Conclusion: Deep learning methods have shown promising potential in acting as an assistant interpreter of radiographic images in patients with Lisfranc malalignment. Developing these algorithms can hasten and improve the accuracy of diagnosis and reduce further costs and burdens on the patients and health care system. Level of Evidence: Level III, case-control Machine Learning study.