Background: Physical inactivity and Type 2 diabetes mellitus (T2DM)���associated inflammatory biomarkers are correlated with poor quality of life (QoL). However, no study has investigated the synergistic effect of physical activity (PA) and lower neutrophil���lymphocyte ratio (NLR) on QoL. Objective: We examined the independent and synergistic effects of PA and inflammatory biomarkers on three domains of QoL in T2DM. Methods: This cross-sectional study included 294 patients with T2DM from community clinics in Indonesia. The 36-item Short Form Survey and a questionnaire about PA engagement were used to measure QoL and metabolic equivalent of task (MET)-hr/week, respectively. Inflammatory biomarkers were measured in fasting blood. Adjusted coefficients �� and 95% confidence interval (CI) were estimated using multiple linear regression. The synergistic effect was analyzed using additive interaction for linear regression. Results: Patients with PA ��� 7.5 MET-hr/week exhibited significantly higher total QoL (�� = 8.41, 95% CI = [6.04, 10.78]) and physical component score (PCS; �� = 13.90, 95% CI = [10.52, 17.29]) than those with PA < 7.5 MET-hr/week. Patients with NLR < 1.940 had significantly higher total QoL (�� = 4.76, 95% CI = [3.41, 6.11]), mental component score (MCS; �� = 2.62, 95% CI = [0.75, 4.49]), and PCS (�� = 6.89, 95% CI = [4.97, 8.82]) than patients with NLR ��� 1.940. PA ��� 7.5 MET-hr/week and NLR < 1.940 exhibited a synergistic effect on total QoL, MCS, and PCS. Conclusions: High PA level and low NLR had a positive synergistic effect on QoL among patients with T2DM.