Background: Lumbar degenerative disc disease (LDDD) is a leading cause of chronic lower back pain; however, a lack of clear diagnostic criteria and solid LDDD interventional therapies have made predicting the benefits of therapeutic strategies challenging. Our goal is to develop machine learning (ML)–based radiomic models based on pre-treatment imaging for predicting the outcomes of lumbar nucleoplasty (LNP), which is one of the interventional therapies for LDDD. Methods: The input data included general patient characteristics, perioperative medical and surgical details, and pre-operative magnetic resonance imaging (MRI) results from 181 LDDD patients receiving lumbar nucleoplasty. Post-treatment pain improvements were categorized as clinically significant (defined as a ≥80% decrease in the visual analog scale) or non-significant. To develop the ML models, T2-weighted MRI images were subjected to radiomic feature extraction, which was combined with physiological clinical parameters. After data processing, we developed five ML models: support vector machine, light gradient boosting machine, extreme gradient boosting, extreme gradient boosting random forest, and improved random forest. Model performance was measured by evaluating indicators, such as the confusion matrix, accuracy, sensitivity, specificity, F1 score, and area under the receiver operating characteristic curve (AUC), which were acquired using an 8:2 allocation of training to testing sequences. Results: Among the five ML models, the improved random forest algorithm had the best performance, with an accuracy of 0.76, a sensitivity of 0.69, a specificity of 0.83, an F1 score of 0.73, and an AUC of 0.77. The most influential clinical features included in the ML models were pre-operative VAS and age. In contrast, the most influential radiomic features had the correlation coefficient and gray-scale co-occurrence matrix. Conclusions: We developed an ML-based model for predicting pain improvement after LNP for patients with LDDD. We hope this tool will provide both doctors and patients with better information for therapeutic planning and decision-making.