Antibody–drug conjugates (ADCs) are promising cancer therapeutics, but optimizing their cytotoxic payloads remains challenging. We present DumplingGNN, a novel hybrid Graph Neural Network architecture for predicting ADC payload activity and toxicity. Integrating MPNN, GAT, and GraphSAGE layers, DumplingGNN captures multi-scale molecular features using both 2D and 3D structural information. Evaluated on a comprehensive ADC payload dataset and MoleculeNet benchmarks, DumplingGNN achieves state-of-the-art performance, including BBBP (96.4% ROC-AUC), ToxCast (78.2% ROC-AUC), and PCBA (88.87% ROC-AUC). On our specialized ADC payload dataset, it demonstrates 91.48% accuracy, 95.08% sensitivity, and 97.54% specificity. Ablation studies confirm the hybrid architecture’s synergy and the importance of 3D information. The model’s interpretability provides insights into structure–activity relationships. DumplingGNN’s robust toxicity prediction capabilities make it valuable for early safety evaluation and biomedical regulation. As a research prototype, DumplingGNN is being considered for integration into Omni Medical, an AI-driven drug discovery platform currently under development, demonstrating its potential for future practical applications. This advancement promises to accelerate ADC payload design, particularly for Topoisomerase I inhibitor-based payloads, and improve early-stage drug safety assessment in targeted cancer therapy development.