Memory consolidation relies on discrete spatial patterns of transcriptional events in the hippocampus. Despite the emergence of single-cell transcriptomic profiling techniques, defined learning-responsive gene expression across subregions of the hippocampus has remained largely unknown. Here, we utilized unbiased sequencing to elucidate transcriptome-wide changes in gene expression in the hippocampus following a learning experience, enabling us to define molecular signatures unique to each hippocampal subregion. We found that the CA1 pyramidal layer, CA1 stratum radiatum, CA1 stratum oriens, CA2/3 pyramidal layer, and dentate gyrus (DG) granular and molecular layers of the dorsal hippocampus exhibit distinct yet overlapping transcriptomic signatures. Our results correlate with conventional whole-tissue transcriptomic approaches, reaffirming the rigor and validity of our findings. While the CA1 region exhibited increased expression of genes related to transcription regulation, the dentate gyrus (DG) showed upregulation of genes associated with protein folding. We demonstrated the functional relevance of subregion-specific gene expression by genetic manipulation of a transcription factor selectively in the CA1 hippocampal subregion, leading to long-term memory deficits. Thus, our work demonstrates the strength of using spatial molecular approaches to reveal transcriptional events across brain regions during memory consolidation.