To evaluate the association between genetic polymorphisms in SOD2 and SOD3 and oral health-related quality of life (OHRQoL). Material and methods: The cohort study included 109 participants, all of whom underwent root canal treatment on a single-rooted maxillary or mandibular tooth with asymptomatic periapical periodontitis. The OHRQoL was assessed using the Oral Health Impact Profile-14 at three intervals: prior to root canal treatment (T0), 7 (T7), and 30 (T30) days post-treatment. Genomic DNA was extracted from buccal cells for genotyping of polymorphisms in SOD2 (rs5746136, rs4880, and rs10370) and SOD3 (rs2855262 and rs13306703) using real-time PCR. Both Univariate and Multivariate Poisson Regression analyses were conducted, with p < 0.05 indicating statistical significance. Results: The rs2855262 polymorphism in the SOD3 gene showed a significant difference in the functional limitation domain in both codominant (p = 0.037) and recessive (p = 0.040) models. The rs13306703 polymorphism in SOD3 demonstrated a significant difference in physical pain [in codominant (p = 0.001) and recessive (p < 0.001) models], psychological discomfort [in codominant (p = 0.002) and recessive (p = 0.002) models], handicap [in codominant (p = 0.011) and dominant (p = 0.015) models], and total score [in codominant (p = 0.011) and recessive (p = 0.007) models]. In the Multivariate Poisson Regression analysis, SOD2 (rs5746136) was associated with the psychological disability domain [in codominant (p = 0.049) and recessive (p = 0.040) models] and SOD3 (rs13306703), in the handicap domain [in codominant (p = 0.028) and dominant (p = 0.037) models]. Conclusions: Genetic polymorphisms in SOD2 and SOD3 genes can influence the OHRQoL response in patients with asymptomatic periapical periodontitis.