Sleep supports a variety of physiological processes, ranging from metabolic to immune system homeostasis, and plays a critical role in cognition and memory. A brief period of sleep loss impairs memory, particularly hippocampus-dependent memories, and alters molecular signaling and synaptic plasticity in the hippocampus. Studies have shown that sleep deprivation (SLD) alters neuronal activation as indicated by broad changes in gene expression signatures and by the altered expression of c-Fos, an immediate early gene (IEG) that functions as a molecular marker of neuronal activity. In the present study, we examined hippocampal subregion-specific c-Fos induction patterns. We find that CA1 pyramidal neurons exhibit the most robust c-Fos induction after SLD. Within CA1, the proximal region, where spatial information is processed and encoded, shows higher c-Fos levels after SLD as compared to the distal region. Using an activity-driven ribosomal tagging system and a repeated SLD model, we identify a specific population of excitatory neurons in area CA1 that are reactivated by repeated SLD. This approach also enables analysis of individual gene expression from c-Fos+ neurons to identify specific molecular signatures of neurons sensitive to repeated sleep loss. In summary, our study provides a detailed view of the activation of hippocampal neurons after SLD, revealing a subset of CA1 pyramidal neurons having higher sensitivity to the effect of sleep loss and laying the groundwork for further research investigating molecular changes in neurons specifically impacted by repeated sleep loss.