Duchenne muscular dystrophy (DMD) is a progressive X-linked neurodegenerative disease caused by loss-of-function mutations in the dystrophin gene, resulting in the complete absence of dystrophin protein. The molecular mechanisms are not fully known, but evidence supporting miR-146a as a suspected driver of chronic inflammation in DMD muscles has been observed as one aspect, such as elevated levels of miR-146a in the muscles of DMD patients and in DMD model mice (mdx). To investigate the role of miR-146a in DMD pathophysiology, mdx mice with genetic deletion of miR-146a were generated (termed mdx-146aX) along with wild-type (WT) containing a double knock-out (WT-146a-/-) serving as a control for background. We performed bulk RNA sequencing of the tibialis anterior muscle of WT, WT-146a-/-, mdx, and mdx-146aX mice. Differential gene expression analysis, gene ontology (GO) analyses, and various gene signatures were utilized to demonstrate a trend of genetic expression towards WT in mdx-146aX muscles. Notably we identified genes involved in interferon-g signaling (Irga6/Iigp), Wnt signaling (Sfrp1), and muscle regeneration (Pcdhb7) that were elevated in mdx and reduced towards WT in mdx-146aX. mdx muscles also showed reductions in genes involved in mitochondrial biogenesis (Mrpl55) and muscle differentiation (Ckdl1) that were increased towards WT levels in mdx-146aX. Additionally, we analyzed an inflammatory gene signature and a myonuclear cell signature further supporting a shift towards WT in mdx-146aX mice. Together, these data provide more context to previously observed improved functionality of mdx-146aX mice and suggest miR-146a could serve as a potential focus for therapeutics considering its role in DMD pathophysiology.