Viral invasion of the host cell causes some of the most dramatic changes in biology. Human cytomegalovirus (HCMV) extensively remodels host cells, altering nuclear shape and generating a cytoplasmic viral-induced assembly compartment (vIAC). How these striking morphology changes occur in the context of host gene regulation is still emerging. Histone variant macroH2A1 is both important for maintaining nuclear integrity and functions to promote herpes simplex virus infection. Therefore, we hypothesized it may also function in cytomegalovirus infection. Here, we discovered that macroH2A1 is necessary for HCMV-induced cellular reorganization and formation of infectious progeny. Using RNA-seq in infected cells, we find that while all viral genes are highly expressed in the absence of macroH2A1, many HCMV-induced host genes are not. Remarkably, hundreds of these HCMV-induced macroH2A1-dependent host genes are associated with a neuronal signature. Further, we find that HCMV immediate early protein, IE1, is both necessary and sufficient to induce these neuronal genes, providing a mechanism of activation. Together, our findings demonstrate that HCMV hijacks a dormant neuronal secretory pathway through chromatin manipulation for efficient virion maturation.