Rizatriptan benzoate (RZB), a first-line therapy for the acute treatment of migraine, requires sensitive and reliable monitoring in pharmaceutical formulations and biological matrices to ensure effective quality control and therapeutic drug monitoring. In this work, a sustainable, novel and cost-effective electrochemical sensor was established for the sensitive determination of RZB by modifying a carbon paste electrode (CPE) with nickel-doped zinc oxide nanoparticles (Ni-ZnO NPs) via a simple precipitation procedure. The prepared nanoparticles were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM) coupled with energy-dispersive X-ray spectroscopy (EDX), and Fourier-transform infrared spectroscopy (FT-IR), confirming their crystalline nature. The Ni-ZnO/CPE demonstrated remarkable electrocatalytic efficiency for RZB oxidation in phosphate buffer solution at pH 6.0. Utilizing differential pulse voltammetry, the sensor showed linearity over the concentration interval of 0.04-20 µM. Moreover, the sensor showed excellent repeatability and intermediate precision, with relative standard deviation (RSD) values below 1.5%. The sensor was effectively employed for RZB detection in tablets and human plasma, exhibiting adequate recovery rates of 99.71-101.26% and 100.22-101.26%, respectively. The suggested approach revealed favorable analytical performance compared with previously reported DPV procedures, offering a lower limit of detection of 0.01 µM and enhanced sensitivity. Moreover, this is the first reported electrochemical method for RZB that combines drug determination with a comprehensive environmental assessment. Environmental sustainability was assessed utilizing modern metrics for greenness, blueness, and whiteness, and the findings revealed an excellent eco-profile with strong compliance with the principles of green analytical chemistry.