Postmenopausal women are significantly predisposed to a multitude of disorders. Laser biostimulation (LB) and a healthy diet have been linked to multiple health benefits. This study aimed to investigate the effect of a combined LB and balanced low-calorie diet (LCD) vs. an LCD alone on insulin resistance (IR), inflammatory biomarkers, and depression score in obese postmenopausal women. In the present study, a total of 66 postmenopausal women, with a mean age of 66.61 ± 4.80 years and a body mass index (BMI) of 35.93 ± 2.67 kg/m2, were randomized into two equal groups. The experimental group received LB and LCD (including 50-60% carbohydrates, 15-20% protein, 20-35% fat, and 25 g of fiber/day plus a restriction of 500-1000 kcal/d), while the control group followed the same diet program only for 12 weeks. Before and after the intervention, IR [measured by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR index)], inflammatory biomarkers [C-reactive protein (CRP), white blood cells (WBCs), lymphocytes, and erythrocyte sedimentation rate (ESR)], and depression level [as assessed by the Hamilton Depression Rating Scale (HAMD-17)] were all measured. Using an intention-to-treat analysis for 60 women who completed the study, the body weight average reduction was -13.14% for the experimental group (p<0.001) vs. -6.36% for the control group (p<0.001). BMI, IR, inflammatory markers, and depression levels were also similarly changed. In postmenopausal obese women, adding LB to a suitable dietary program provides the most significant benefit in terms of lowering IR, metabolic inflammation, and depression.