Background: Periodontitis, the second most common reason for tooth loss in adults, is a chronic inflammatory condition that increases the prevalence of cancer by inhibiting apoptosis and promoting tumor cell growth. However, it is still debatable if tooth loss is an important risk factor in oral cancer (OC). The aim of this systematic review is to analyze the relationship between tooth loss and the probability of developing head-and-neck cancer and also to see if there is an association between tooth loss, periodontitis, and the risk of OC. Materials and Methods: Studies that depicted a link between tooth loss and OC (till 2017) were searched from online databases accompanied by a thorough manual search of relevant journals. Data were collected from eligible studies, and meta-analysis was carried out using the Meta-Analysis software. The effect of various inclusions was assessed by sensitivity and subgroup analysis. Publication bias was also evaluated. Results: The meta-analysis consisted of 15 publications. When the number of teeth lost was counted, there was significant variability (I2 = 98.7%, P = 0.0001). When more than 15 teeth were missing in a subgroup analysis, there was a 2.4 times greater risk of OC (odds ratio: 2.496, 95% confidence interval [CI] = 2.067–3.015, P = 0.001) with no heterogeneity (I2 = 0.00%, 95% CI for I2 = 0.00–68.98). Subgroup analysis revealed that there was no evidence of publication bias. Conclusion: It was concluded that tooth loss can increase the OC risk by nearly 2 folds. However, large-scale population-based studies are needed to substantiate the findings.