Objectives Chronic periodontitis (CP) is a common inflammatory disorder with a considerable impact of genetic variations in the interleukin family on predisposition to this disease. This study aimed to investigate the association between the -592C>A polymorphism of the interleukin 10 (IL-10) gene with CP risk in an Iranian population. This experimental study was followed by a meta-analysis and in silico examination. Methods In a case-control study, 270 subjects, including 135 patients with CP and 135 healthy controls, were enrolled. The -592C>A genotyping was performed using the PCR-RFLP method. In the meta-analysis, valid databases were systematically searched to identify relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were computed to examine the association between -592C>A and CP. In silico analysis was conducted using bioinformatics tools to evaluate the impact of the -592C>A polymorphism on IL-10 gene function. Results Our case-control study revealed a significant association between polymorphism and CP risk. Overall, we found significant associations between -592C>A genetic variation and CP and stratified meta-analysis. In silico analysis revealed that this polymorphism could change the pattern of the transcription binding site upstream of the IL-10 gene. It may also alter the hsa-miR-101-3p miRNA-targeted sequence upstream of IL-10. Conclusions Based on our results, the -592C>A variation in IL-10 may be a genetic risk factor for susceptibility to chronic periodontitis. However, further studies in different ethnicities and results adjusted for clinical and demographic characteristics are needed to obtain more accurate deductions.