A novel modified glassy carbon electrode based on poly aspartic acid-Fe3O4 nanoparticle / multi-walled carbon nanotubes composite (PAA-FeNPs-MWCNTs/GCE) was developed and used as an efficient sensor for simultaneous determination of piroxicam (PRX) and clopidogrel (CLO) in the presence of uric acid (UA). Response surface methodology (RSM) was utilized in optimization of the effects of various operating variables on the voltammetric response of PRX and CLO suggesting that the amount of PAA-FeNPs in the modifier matrix (% PAA-FeNPs), the solution pH and the accumulation time (t) were the three most important operating factors. The central composite design (CCD) as a response surface approach was applied for obtaining the optimum conditions as well as the maximum heights for oxidation peak currents of PRX and CLO. The differential pulse voltammetry (DPV) results showed that under the optimal experimental conditions the obtained anodic peak currents were linearly proportional to concentration in the range of 0.2-80 μM with a detection limit (S/N = 3.0) of 45 nM for PRX and in the range of 0.4-48 μM and with a detection limit of 76 nM for CLO. The applicability of the proposed method was successfully demonstrated for simultaneous determination of these compounds in human urine and blood serum samples.