A simple, rapid, isocratic, high-performance liquid chromatography (RP-HPLC) method has been developed for the first time for simultaneous determination of ACE inhibitors (captopril, lisinopril and enalapril) and diclofenac sodium in bulk drugs, pharmaceutical products and human serum. The separation was performed on a Purospher Start C18 (250cm x 4.6mm, 5µm) and Hypersil ODS (25cm x 4.6mm 5µm ) column using methanol–water as mobile phase 80:20 (v/v) and 60:40 (v/v) as diluent. The pH of mobile phase was adjusted to 3.0 with ortho-phosphoric acid, flow rate was adjusted to 1 mLmin-1 at room temperature and analytes peaks were observed using UV detector at 220 nm. The retention times of captopril, lisinopril, enalapril and diclofenac sodium were 2.5, 3.8, 4.5 and 5 min and LLOD, LLOQ were 1, 4, 2, 6, 3 and 12, 8, and 14 ngmL-1 respectively. The method was validated according to ICH guidelines. The linearity of the method was studied over the concentration range of 2.5–50 µgmL-1 for ACE inhibitors and diclofenac sodium, where it demonstrated good linearity with r = 0.9998, 0.9999, 0.9997, and 0.9998 (n = 6), respectively. The HPLC method presented here shows an easy but reliable and precise analysis of the antihypertensive drugs captopril, lisinopril, enalapril, and diclofenac sodium. The values for LLOD, precision of RT, precision of area and linearity shows good performance of the analysis. The developed method was successfully applied to quantitate, the three ACE inhibitors and diclofenac sodium in pharmaceutical formulations and human serum.