Title: A new photoreceptor-inspired CNN layer enables deep learning models of retina to generalize across lighting conditions. Abstract: As we move our eyes, and as lighting changes in our environment, the light intensity reaching our retinas changes dramatically and on multiple timescales. Despite these changing conditions, our retinas effortlessly extract visual information that allows downstream brain areas to make sense of the visual world. Such processing capabilities are desirable in many settings, including computer vision systems that operate in dynamic lighting environments like in self-driving cars, and in algorithms that translate visual inputs into neural signals for use in vision-restoring prosthetics. To mimic retinal processing, we first require models that can predict retinal ganglion cell (RGC) responses reliably. While existing state-of-the-art deep learning models can accurately predict RGC responses to visual scenes under steady-state lighting conditions, these models fail under dynamic lighting conditions. This is because changes in lighting markedly alter RGC responses: adaptation mechanisms dynamically tune RGC receptive fields on multiple timescales. Because current deep learning models of the retina have no in-built notion of light level or these adaptive mechanisms, they are unable to accurately predict RGC responses under lighting conditions that they were not trained on. We present here a new deep learning model of the retina that can predict RGC responses to visual scenes at different light levels without requiring training at each light level. Our model combines a fully trainable biophysical front end capturing the fast and slow adaptation mechanisms in the photoreceptors with convolutional neural networks (CNNs) capturing downstream retinal processing. We tested our model’s generalization performance across light levels using monkey and rat retinal data. Whereas conventional CNN models without the photoreceptor layer failed to predict RGC responses when the lighting conditions changed, our model with the photoreceptor layer as a front end fared much better in this challenge. Overall, our work demonstrates a new hybrid approach that equips deep learning models with biological vision mechanisms enabling them to adapt to dynamic environments.