For the simultaneous quantification of azithromycin (AZI), fluconazole (FLU), and secnidazole (SEC) in Combi-kit amount from tablets, a quick, stable high-performance thin-layer chromatography (HPTLC) method was developed and validated. A mixture of toluene‒ethyl acetate‒methanol‒formic acid‒ammonia (3:6:3:0.1:0.1, V/V) was used as the mobile phase; HPTLC silica gel 60 F254 plates were used as stationary phase. Densitometric scanning was done at 209 nm wavelength with a CAMAG TLC Scanner 3. The International Council for Harmonisation requirements were followed in the validation of the developed method. The RF values of AZI, FLU, and SEC were found to be 0.62, 0.78, and 0.68. AZI (R2 = 0.9935), FLU (R2 = 0.9959), and SEC (R2 = 0.9990) all had good linear relationships with their regression coefficient in the drug concentration range of 40‒80 µg/band, 600‒1200 ng/band, and 4‒8 µg/band, respectively. The limit of detection (LOD) values for AZI, FLU, and SEC were found to be 0.174 µg/band, 0.842 ng/band, and 0.006 µg/band, respectively. The limit of quantification (LOQ) values for AZI, FLU, and SEC were found to be 0.530 µg/band, 2.553 ng/band, and 0.018 µg/band. Under acidic, basic and oxidative degradation conditions, it was found that AZI, FLU, and SEC showed well resolved peaks derived from the drug’s active ingredient. It came to light that the method employed was both repeatable and selective for identifying AZI, FLU, and SEC at the same time. The method can be used to indicate stability because it can effectively distinguish the medicines from their degradation products.