Objectives To evaluate the expression of proteins related to activation of the NLRP3 inflammasome in patients with chronic periodontitis (CP) and type 2 diabetes mellitus (T2D), and to determine whether the exacerbated periodontal pathological process observed in diabetic patients is related to its upregulation. Materials and Methods We performed an observational, analytical, cross‐sectional study in three study groups: individuals systemically and orally healthy, and patients with CP with and without T2D. Gingival biopsies were taken from the three study groups. The expression of mRNAs for CASP1, NLRP3 and ASC was detected using real‐time PCR, and the expression of NLRP3 and ASC proteins was determined by immunohistochemistry. The quantification of IL‐18 and IL‐1β was determined in the gingival crevicular fluid using ELISA. The results were analysed by ANOVA followed by Tukey's test to compare differences between individual groups. Results Patients with CP and uncontrolled T2D presented severe periodontal disease and inflammation (PPD, p = 0.0072; CAL, p = 0.0480; bone loss, p = 0.0088), higher levels of CASP1 mRNA expression (p = 0.0026), a stronger pattern of staining for NLRP3 and ASC proteins in the epithelium and connective tissues, and significantly higher production of IL‐18 (p = 0.0063) and IL‐1β (p = 0.0018) in comparison with healthy or CP subjects. Conclusion The upregulation of genes and proteins involved in the activation of the NLRP3 inflammasome components in patients with periodontitis and uncontrolled T2D suggests a possible role in the more severe pathological processes leading to destruction of periodontal tissues observed in these patients.