UVB radiation is the main factor causing hyperpigmentation. Secretome hypoxic mesenchymal stem cells (S-HMSCs) contain bioactive soluble molecules such as growth factors and anti-inflammatory cytokines that can prevent melanin synthesis and induce collagen formation. However, the role of S-HMSCSs on IL-6, p50, and p65 gene expression in hyperpigmentation is still unclear. This study aimed to determine the effect of administration of S-HMSCSs gel on the expression of IL-6, p50, and p65 in a hyperpigmented rat skin model induced by UVB light exposure. Twenty-five male Wistar rats of hyperpigmented were created as an animal model under exposed to UVB 6 times in 14 days at 302 nm with a MED of 390 mJ/cm2. The animal was randomly assigned into five groups consisting of two treatment groups (treated by S-HMSCs at a 100µL as T1 and 200µL as T2 on bases gel) for 14 days, control groups (UVB-irradiation), sham (negative control), and base gel groups. On the 14th day, IL-6, p50, and p65 were terminated and analyzed using qRT-PCR. Statistical analysis will perform using one way ANOVA followed with post hoc LSD test. Analysis of IL-6 (8.59± 3.32), p50 (4.35±2.27), and p65 (4.09±1.82) gene expression in the treatment group decreased along with the increase in the concentration of S-MSCs compared to the control group. In conclusion, the administration of S-HMSCs gel is expected to affect the speed of decreasing the hyperpigmentation process significantly.