A successful attempt has been made to develop and validate a stability-indicating high-performance thin-layer chromatography (HPTLC) method for the simultaneous estimation of empagliflozin and metformin in pharmaceutical formulation. Excellent separation between drugs and degradation products was achieved by using toluene‒methanol‒ammonia‒glacial acetic acid (7.2:2.6:0.1:0.1, V/V) as the mobile phase and pre-coated silica gel GF254 plates as the stationary phase. Detection was done at 230 nm in absorbance mode. Retention factors (RF) were found to be 0.15 ± 0.02 and 0.48 ± 0.02 for metformin and empagliflozin, respectively. Pharmaceutical formulation was analyzed by the developed method and % drug contents were determined. The % drug contents were found to be 98.65 ± 1.61 and 99.54 ± 1.34% w/w for metformin and empagliflozin, respectively. The developed method was validated for specificity, linearity, range, accuracy, precision, detection limit, quantitation limit and robustness according to the International Council for Harmonisation (ICH) guidelines. The drugs were subjected to forced degradation under different conditions like hydrolysis (acid, base and neutral), oxidation, thermal and photo-degradation. Empagliflozin was found to be susceptible to acid and base hydrolysis as well as oxidative degradation. Metformin was found to be susceptible to alkaline hydrolysis under optimized forced degradation conditions. Degradation products generated were characterized by liquid chromatography coupled with electrospray ionization‒quadrupole-time of flight‒tandem mass spectrometry (LC‒ESI‒QTOF‒MS/MS) studies and structures of degradation products were proposed. From the stability studies, it was concluded that empagliflozin should be protected from acid, alkaline and oxidative stress to enhance stability. © 2022, Akadémiai Kiadó, Budapest, Hungary.