Background After the COVID-19 pandemic, the conflict between limited mental health care resources and the rapidly growing number of patients has become more pronounced. It is necessary for psychologists to borrow artificial intelligence (AI)–based methods to analyze patients’ satisfaction with drug treatment for those undergoing mental illness treatment. Objective Our goal was to construct highly accurate and transferable models for predicting the satisfaction of patients with mental illness with medication by analyzing their own experiences and comments related to medication intake. Methods We extracted 41,851 reviews in 20 categories of disorders related to mental illnesses from a large public data set of 161,297 reviews in 16,950 illness categories. To discover a more optimal structure of the natural language processing models, we proposed the Unified Interchangeable Model Fusion to decompose the state-of-the-art Bidirectional Encoder Representations from Transformers (BERT), support vector machine, and random forest (RF) models into 2 modules, the encoder and the classifier, and then reconstruct fused “encoder+classifer” models to accurately evaluate patients’ satisfaction. The fused models were divided into 2 categories in terms of model structures, traditional machine learning–based models and neural network–based models. A new loss function was proposed for those neural network–based models to overcome overfitting and data imbalance. Finally, we fine-tuned the fused models and evaluated their performance comprehensively in terms of F1-score, accuracy, κ coefficient, and training time using 10-fold cross-validation. Results Through extensive experiments, the transformer bidirectional encoder+RF model outperformed the state-of-the-art BERT, MentalBERT, and other fused models. It became the optimal model for predicting the patients’ satisfaction with drug treatment. It achieved an average graded F1-score of 0.872, an accuracy of 0.873, and a κ coefficient of 0.806. This model is suitable for high-standard users with sufficient computing resources. Alternatively, it turned out that the word-embedding encoder+RF model showed relatively good performance with an average graded F1-score of 0.801, an accuracy of 0.812, and a κ coefficient of 0.695 but with much less training time. It can be deployed in environments with limited computing resources. Conclusions We analyzed the performance of support vector machine, RF, BERT, MentalBERT, and all fused models and identified the optimal models for different clinical scenarios. The findings can serve as evidence to support that the natural language processing methods can effectively assist psychologists in evaluating the satisfaction of patients with drug treatment programs and provide precise and standardized solutions. The Unified Interchangeable Model Fusion provides a different perspective on building AI models in mental health and has the potential to fuse the strengths of different components of the models into a single model, which may contribute to the development of AI in mental health.