Four simple, reproducible and rapid stability-indicating spectrophotometric methods were developed and efficiently applied for the estimation of zonisamide (anticonvulsant drug) in the presence of its oxidative degradation product. The degradation pathway was clearly illustrated and the structure of the degradation product was elucidated by infrared and mass spectroscopy. The proposed methods were the direct spectrophotometric method (D0), the first derivative method (D1), the ratio difference method (RD) and, finally, the first derivative of the ratio spectra method 1DD. Good sensitivity and high reproducibility were obtained via the developed methods. Linearity ranges were 5–40 μg/mL for the first method and 2–40 μg/mL for the other three methods. Mean recovery percentages of the methods were 100.12 ± 0.590 for D0, 99.97 ± 0.606 for D1, 99.88 ± 0.546 for RD, and 99.94 ± 0.619 for 1DD. The specificity of the methods was investigated by analyzing synthetic mixtures of different percentages of zonisamide and its oxidative degradation product. The proposed methods were validated in accordance with ICH guidelines. Statistical analysis showed no significant differences in comparison with the official method. [ABSTRACT FROM AUTHOR]