Neophobia (“fear of novelty”) is often repeatable within individuals and across contexts, suggesting it reflects an animal’s underlying exploratory temperament, and neophobia can affect the ability of wildlife to adapt to new challenges and opportunities. Despite the ubiquity and importance of this personality trait, however, the molecular mechanisms underlying neophobia are poorly understood. We first screened a group of wild-caught house sparrows (Passer domesticus) for neophobia in the lab using novel object tests. We then selected a subset of the most and least neophobic individuals (n=3 of each) and used RNAseq to assess transcriptomes of four brain regions involved in learning, threat perception, and executive function in birds: striatum, hippocampus, nucleus taeniae of the amygdalae (TnA), and nidopallium caudolaterale (NCL). We found significant overall effects of brain region, phenotype (neophobic vs. non-neophobic), and a brain region by phenotype interaction. Comparing neophobic and non-neophobic birds revealed constitutive differentially expressed genes (DEGs) in three brain regions we examined: hippocampus (~12% of the transcriptome), striatum (4%) and NCL (3%). Two ontology-based analyses (Gene Ontology and Eukaryotic Orthologous Group annotations) revealed that the majority of enriched terms across all brain regions were in transcripts upregulated in neophobic birds, and were broadly distributed across structural, signaling, and metabolic processes. These results suggest that some behavioral differences in neophobic and non-neophobic birds may be due to underlying DEGs in the brain that create structural, signaling, and metabolic differences between the two phenotypes.