A new enrichment and determination method involving HPLC-DAD analysis following magnetic solid-phase extraction (MSPE) was developed to detect trace amounts of two antidepressant drugs, namely, duloxetine (DUL) and vilazodone (VIL). In this study, a solid-phase sorbent was newly synthesized for use in the MSPE and its characterization was carried out by scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy and X-ray diffraction (XRD) techniques. In this proposed method, DUL and VIL molecules were enriched using newly synthesized magnetic-based nanoparticles in the presence of pH 10.0 buffer and desorbed with acetonitrile to a smaller volume prior to chromatographic determinations. After experimental variables were optimized, the VIL and DUL molecules were analyzed at wavelengths of 228 nm for DUL and 238 nm for VIL with isocratic elution of methanol, trifluoroacetic acid (TFA) (0.1%), and acetonitrile (10 : 60 : 30). The detection limits obtained under optimized conditions were 1.48 ng mL−1and 1.43 ng mL−1, respectively. The %RSD values were found to be lower than 3.50% with model solutions containing 100 ng mL−1(N:5). Finally, the developed method was successfully applied to wastewater samples and simulated urine samples, and quantitative results were obtained in the recovery experiments.