The present manuscript describe simple, sensitive, rapid, accurate, precise and economical first derivative spectrophotometric method for the simultaneous determination of dicloxacillin and cefpodoxime proxetil in combined tablet dosage form. The derivative spectrophotometric method was based on the determination of both the drugs at their respective zero crossing point (ZCP). The first order derivative spectra was obtained in methanol and the determinations were made at 233.8 nm (ZCP of cefpodoxime proxetil) for dicloxacillin and 321 nm (ZCP of dicloxacillin) for cefpodoxime proxetil. The linearity was obtained in the concentration range of 10-80 μg/ml for dicloxacillin and 4-32 μg/ml for cefpodoxime proxetil. The mean recovery was 100.70 ± 0.38 and 99.90 ± 0.36 for dicloxacillin and cefpodoxime proxetil, respectively. The method was found to be simple, sensitive, accurate and precise and was applicable for the simultaneous determination of dicloxacillin and cefpodoxime proxetil in pharmaceutical tablet dosage form. The results of analysis have been validated statistically and by recovery studies.