Drosophila melanogaster females undergo a variety of post-mating changes that influence their activity, feeding behavior, metabolism, egg production and gene expression. These changes are induced either by mating itself or by sperm or seminal fluid proteins. In addition, studies have shown that axenic females-those lacking a microbiome-have altered fecundity compared to females with a microbiome, and that the microbiome of the female's mate can influence reproductive success. However, the extent to which post-mating changes in transcript abundance are affected by microbiome state is not well-characterized. Here we investigated fecundity and the post-mating transcript abundance profile of axenic or control females after mating with either axenic or control males. We observed interactions between the female's microbiome and her mating status: transcripts of genes involved in reproduction and genes with neuronal functions were differentially abundant depending on the females' microbiome status, but only in mated females. In addition, immunity genes showed varied responses to either the microbiome, mating, or a combination of those two factors. We further observed that the male's microbiome status influences the fecundity of both control and axenic females, while only influencing the transcriptional profile of axenic females. Our results indicate that the microbiome plays a vital role in the post-mating switch of the female's transcriptome.