Aim To evaluate the expression of the NLRP3 inflammasome and IL-1β cytokine in the progression of periapical lesions in wild-type (WT) and TLR2 knockout (KO) mice. Materials and Methods An experimental investigation was carried out, considering 28 WT and 27 TLR2-KO mice ( N = 55). All periapical lesions were induced in mandibular first molars, and mice were randomly euthanized after 7, 21, and 42 days of pulpal exposure ( n = 8-10 per group/period). Microscopic analysis was carried out using hematoxylin-eosin staining and immunohistochemistry for NLRP3 inflammasome and IL-1β cytokine expressions. The significance level was set at 5%. Results Pulpal exposure triggered an inflammatory reaction in both animal models. Regarding periapical bone resorption, the lesion area was significantly larger in TLR2-KO mice compared to WT after 21 days ( p = 0.006). Addressing NLRP3 inflammasome immunostaining, the stained area was significantly larger in WT mice compared to TLR2-KO after 21 days ( p = 0.006) and 42 days ( p = 0.003). Ultimately, in relation to the IL-1β cytokine expression, more positive cells were significantly observed in TLR2-KO mice compared to WT after 42 days ( p = 0.003). Correlating the expression of NLRP3 inflammasome and IL-1β cytokine, a significant, positive and weak correlation was observed in WT mice ( p = 0.039, ρ = 0.393), which was not observed in TLR2-KO ( p = 0.384). Conclusion Periapical bone resorption and the expression of IL-1β cytokine were increased in the absence of TLR2, suggesting a protective role of this receptor against osteolysis that was not mediated by the NLRP3 inflammasome.