Medication-related osteonecrosis of the jaw (MRONJ) is intractable and severely affects a patient's quality of life. Although many cases of MRONJ have been reported in the past decade, the disease pathophysiology is unclear and there are no evidence-based therapeutic strategies. MRONJ usually features bone inflammation and infection. Prior studies that explored the association between MRONJ and microbial infection used the culture-based approach, which is not applicable to hundreds of unculturable taxa in the human oral microbiome, or 16S ribosomal RNA gene sequencing, which does not provide quantitative information of the abundance of specific taxa, and information of the presence, abundance, and function of specific genes in the microbiome. Here, deep shotgun metagenome sequencing (>10 Gb per sample) of bulk DNA extracted from saliva of MRONJ patients and healthy controls was performed to overcome these limitations. Comparative quantitative analyses of taxonomic and functional composition of these deep metagenomes (initially of 5 patients and 5 healthy controls) revealed an average 10.1% increase of genus Actinomyces and a 33.2% decrease in genus Streptococcus normally predominant in the human oral microbiota. Pan-genome analysis identified genes present exclusively in the MRONJ samples. Further analysis of the reads mapping to the genes in the extended dataset comprising five additional MRONJ samples and publicly available dataset of nine healthy controls resulted in the identification of 31 genes significantly associated with MRONJ. All these genes were encoded by Actinomyces genomic regions. Of these, the top two abundant genes were almost exclusively encoded by Actinomyces among usual taxa in the human oral microbiota. The potential relationships of these key genes with the disease are discussed at molecular level based on the literature. Although the sample size was small, this study will aid future studies to verify the data and characterize these genes in vitro and in vivo to understand the disease mechanisms, develop molecular targeted drugs, and for early stage screening and prognosis prediction.