Periodontitis is a chronic inflammatory oral disease that affects approximately 42% of adults 30 years of age or older in the United States. In response to microbial dysbiosis within the periodontal pockets surrounding teeth, the host immune system generates an inflammatory environment in which soft tissue and alveolar bone destruction occur. The objective of this study was to identify diagnostic biomarkers and the mechanistic drivers of inflammation in periodontitis to identify drugs that may be repurposed to treat chronic inflammation. A meta-analysis comprised of two independent RNA-seq datasets was performed. RNA-seq analysis, signal pathway impact analysis, protein-protein interaction analysis, and drug target analysis were performed to identify the critical pathways and key players that initiate inflammation in periodontitis as well as to predict potential drug targets. Seventy-eight differentially expressed genes, 10 significantly impacted signaling pathways, and 10 hub proteins in periodontal gingival tissue were identified. The top 10 drugs that may be repurposed for treating periodontitis were then predicted from the gene expression and pathway data. The efficacy of these drugs in treating periodontitis has yet to be investigated. However, this analysis indicates that these drugs may serve as potential therapeutics to treat inflammation in gingival tissue affected by periodontitis.