In the face of the unrelenting challenge posed by earthquakes—a natural hazard of unpredictable nature with a legacy of significant loss of life, destruction of infrastructure, and profound economic and social impacts—the scientific community has pursued advancements in earthquake early warning systems (EEWSs). These systems are vital for pre-emptive actions and decision-making that can save lives and safeguard critical infrastructure. This study proposes and validates a domain-informed deep learning-based EEWS called the hybrid earthquake early warning framework for estimating response spectra (HEWFERS), which represents a significant leap forward in the capabilities to predict ground shaking intensity in real-time, aligning with the United Nations’ disaster risk reduction goals. HEWFERS ingeniously integrates a domain-informed variational autoencoder for physics-based latent variable (LV) extraction, a feed-forward neural network for on-site prediction, and Gaussian process regression for spatial prediction. Adopting explainable artificial intelligence-based Shapley explanations further elucidates the predictive mechanisms, ensuring stakeholder-informed decisions. By conducting an extensive analysis of the proposed framework under a large database of approximately 14 000 recorded ground motions, this study offers insights into the potential of integrating machine learning with seismology to revolutionize earthquake preparedness and response, thus paving the way for a safer and more resilient future.