Two novel analytical techniques have been introduced for the determination of trazodone hydrochloride (TZD HCl) in its solutions. The first is a facile potentiometric technique involving the fabrication of a new sensor based on a neutral carrier, di-benzo-30-crown-10, embedded in a plasticized poly (vinyl chloride) membrane using o￾nitrophenyl octyl ether as a plasticizer. This sensor exhibits a reliable response, giving a cationic slope of 57 ± 0.3 mV per decade of concentration across a TZD HCl concentration range of (1 × 10− 4 -1 × 10− 1 mol L− 1 ). It offers a response time of 30 s, a detection limit of (6 × 10− 5 mol L− 1 ), and a lifespan of approximately 9 weeks. The sensor demonstrates high selectivity for TZD HCl over various cations and cationic drug. Optimal pH range for operation is (2.30–5.40) for both TZD HCl concentrations of (1 × 10− 2 mol L− 1 ) and (1 × 10− 3 mol L− 1 ). It demonstrates a successful application to the quantification of TZD HCl in pharmaceutical dosage forms. The second technique is a chromatographic approach utilizing a newly developed HPLC system with a Hypersil BDS C18 column (150 × 4.6 mm, 5 μm pore size). The mobile phase consists of ethanol and 0.03 mol L− 1 ammonium acetate buffer in a 50:50 (v/v) ratio (pH 6), delivered via isocratic elution. A 1.00 mL/min flow rate and a 20.00 μL injection volume are employed. Detection is performed using a fluorescence detector with excitation and emission wavelengths of 320 nm and 480 nm, respectively. This method demonstrates good linearity over the range of TZD HCl concentrations of (0.16–4.00 μg/mL). It also achieves high accuracy and precision in the quantification of TZD HCl in its pure form, pharmaceutical formulations, and plasma samples. These methods achieve good agreement with the principles of green and white analytical chemistry, so, they can therefore be applied safely and simply