To investigate the causal relationship between oral infectious diseases and lacunar stroke (LS) and to identify the role of interleukin-1α (IL-1α), interleukin-6 (IL-6), tumor necrosis factor (TNF), and C-reaction protein (CRP) as potential mediators. The meta-analysis incorporating cross-sectional studies was carried out. Additionally, two-sample Mendelian randomization (MR) analysis was performed to explore the associations between genetically predicted oral infectious diseases (including dental caries, periodontitis, and pulp and periapical diseases) and lacunar stroke, utilizing summary-level data from genome-wide association studies (GWAS). This was followed by a mediation analysis to explore the role of IL-1α, IL-6, TNF, and CRP. Meta-analysis suggested that individuals with periodontitis have a 5.16 times higher risk of developing LS compared to those without periodontitis (95%CI 3.68-7.24). Genetically predicted pulp and periapical diseases (Odds ratios [OR]: 1.20, 95% CI 1.03-1.41) and periodontitis (OR: 1.24, 95%CI 1.03-1.49) showed a moderate association with LS. However, the mediation analysis yielded negative results. The evidence derived from both the MR study and the meta-analysis suggested a potential association between periodontitis and LS. These findings indicated that periodontitis might play a role in the development of LS. However, given the limitations inherent in our research, further studies are necessary to validate these conclusions.