The aim of the investigation was to develop and validate a reversed-phase high-pressure liquid chromatography (RP-HPLC) method for the simultaneous estimation of etodolac and 5-FU in bulk and coated tablet dosage form. The method was validated in terms of linearity, precision, accuracy, and specificity, LOD, and LOQ according to ICH guidelines. The standard instrument parameters were optimized using C18 reverse phase Inertsil® ODS (250 × 4.6 mm, 5µ particle size) column with system equipped with photodiode array (PDA) detector. An optimized ratio of mobile phase in RP-HPLC under low pressure gradient mode comprising of 60:40 % v/v of acetonitrile and di-potassium hydrogen phosphate buffer (pH 6.4; 25 mM), provided sharp peaks (having adequate molar absorptivity at λmax of 280 nm) with short retention time of 4.3+/-0.2 and 11.5+/-0.3 min for 5-FU and etodolac, respectively. Results indicated the method was linear, precise, accurate, rugged and robust with RSD values <2%. The percentage recoveries of both the drugs were within the limits of 90-110% at various spiked concentrations. The proposed method was found to be highly effective and could be successfully employed for the quantification of 5-FU and ETD in bulk drug and tablet formulations for routine analysis.