Wastewater-based epidemiology (WBE) represents a powerful technique for quantifying the attenuation characteristics and consumption of pharmaceuticals. In addition to WBE, no further methods have been developed to assess the wastewater stability related to antidepressants (ADs). In this study, the biodegradability, solubility, and adsorption or partition of 66 ADs were objectively scored according to the relevant guidelines of the Organisation for Economic Cooperation and Development. An assessment framework and the MSSL-RealFormer classification model of ADs wastewater stability were constructed based on physicochemical properties to predict the ADs wastewater stability and the quantitative structure-activity relationship. The constructed MSSL-RealFormer classification model exhibited a markedly higher prediction accuracy than traditional methods. Furthermore, 15 high-stable ADs in wastewater with low biodegradability, high solubility, and low adsorption or partition were identified. SHapley Additive exPlanation method demonstrated that group hydrophobicity, electrostatic and van der Waals forces exerted a significant influence on the ADs wastewater stability. And molecular stability was found to be significantly correlated with the ADs wastewater stability. A combination of density functional theory and MSSL-RealFormer classification model was employed to identify 17 high-stable transformation products of nine medium- and low-stable ADs in wastewater. The Ecological Structure Activity Relationships model demonstrated that bupropion, tapentadol and chlorpheniramine exhibited significant acute toxicity to the aquatic food chain. In this study, a novel deep learning model was constructed to rapidly screen the correlation between the ADs wastewater stability and their molecular structures. It is anticipated to prove a favorable tool for optimizing the wastewater stability screening of pharmaceuticals.