A stability indicating gradient RP-HPLC method is developed for simultaneous determination of ibuprofen and famotidine. Separation of degradants, ibuprofen and famotidine was carried out on Qualisil BDS C8 column (250 × 4.6 mm, 5 µm) using a mobile phase gradient consisting of methanol and water pH 3.0 at a flow rate of 1 mL/min. The detection and reference wavelengths were set at 263 nm (4 nm bandwidth) and 360 nm (80 nm bandwidth), respectively. Intentional degradation of ibuprofen and famotidine was attempted at stress condition of hydrolytic (refluxed at 80ºC for 1 h), acid (5M HCl, refluxed at 80ºC for 1 h), base (5M NaOH, refluxed at 80ºC for 1 h), oxidation (15% H2O2, for 6 h at 30 ºC) and sunlight (exposed for 4 h). Degradants were eluted up to ~ 26 min whereas famotidine and ibuprofen shows retention at 6.34 ± 1.53 and 21.76 ± 0.38 min respectively. Drug-drug interaction study was also performed. The proposed method was able to separate the formed sulfamide impurity which is a major degradation product of famotidine - ibuprofen combination mixture when kept at accelerated condition (40ºC ± 75% RH for 30 days). The method obeys Beer’s law in the concentration range of 3-21 µg/mL for ibuprofen (r2=0.9998) and 0.1-0.7 µg/mL for famotidine (r2=0.9999). The assay result of synthetic mixture was found to be 99.13 ± 0.14 and 100.73 ± 0.57 for ibuprofen and famotidine, respectively. The proposed method was validated as per ICH Q2 (R1) analytical method validation guidelines. The percentage recovery was found to be 96.55 ± 1.83 and 102.83 ± 0.85 for ibuprofen and famotidine, respectively. The results of present study clearly shown that the proposed method was specific as ibuprofen and famotidine were estimated in presence of their acidic, alkaline, oxidative, hydrolytic and photolytic degradation products and it may be effectively applied for estimating the content of ibuprofen and famotidine in pharmaceutical formulation.