Background: Diaper rash requires topical preparation that minimizes friction on inflamed infant skin. A spray gel was selected for hygienic, low-contact application, while peppermint oil, Virgin Coconut Oil (VCO), and lemon oil were combined for their complementary anti-inflammatory, skin-barrier-supporting, and antioxidant properties.Objective: This study aimed to formulate and evaluate an anti-inflammatory spray gel containing peppermint oil, VCO, and lemon oil, with a focus on the relationship between formula composition, physical quality, and in vitro anti-inflammatory activity. Method: This laboratory-based experimental study prepared seven spray gel formulations using Carbopol-940 and HPMC as gel-forming agents. Data were collected through organoleptic observation, homogeneity, pH, spray pattern, adhesion-spreadability, mechanical stability, and anti-inflammatory activity testing using the bovine-serum-albumin method for inhibiting protein denaturation. The data were analyzed descriptively, while anti-inflammatory activity was assessed based on percentage inhibition and IC₅₀ values. Results: The results indicated that all formulations were homogeneous, mechanically stable, and had pH values ranging from 5.38 to 6.98. All formulations demonstrated anti-inflammatory activity, with Formula F3 showing the strongest effect, indicated by the lowest IC₅₀ value of 1.933 µg/mL. Conclusion: These findings suggest that spray gel containing natural bioactive ingredients has potential as a topical anti-inflammatory candidate for diaper rash and contributes to the development of natural-based pharmaceutical formulations.