Synthetic cathinones are a class of new psychoactive substances (NPS), an emerging group of analogues to traditional illicit drugs which are functionalized to circumvent legal regulations. The analytical investigation of NPS by traditional methods, such as gas chromatography-mass spectrometry (GC-MS), is challenging because newly emerging NPS may not yet appear in spectral libraries and because of the inability to determine certain positional isomers. Low-field or “benchtop” proton nuclear magnetic resonance spectroscopy (NMR) is an alternative that provides significant qualitative information but is particularly susceptible to matrix interferences. To this end, the development of a Sequential Injection Analysis (SIA) method which uses solid-phase extraction (SPE) to remove interfering matrix components prior to NMR determination is described. Factors including the type of SPE sorbent, column dimensions, and sample loading and elution conditions were examined. Several cathinone simulants (primary, secondary, and tertiary amines), “DEA exempt” cathinone standards, as well as authentic case samples were studied. The selectivity of the SIA-NMR-UV method was investigated against a broad range of “cutting agents” and was found to successfully remove all compounds tested with the exception of other basic drugs (e.g., acetaminophen). The limit of detection and reproducibility of the method were optimized using a Plackett-Burman screening design and Sequential Simplex optimization. Using a UV detector for dual (in series) quantification, the multivariate-optimized method produced a method limit of detection (3σ) for the cathinone simulant Phenylpropanolamine (PPA) of 23 μmol L−1, and a calibration model, in terms of UV peak area, of Area = 0.19 PPA, mmol L−1 – 0.04. The optimized method generated ~2 mL of waste per day, and had a footprint of ~1 m2 Finally, the multivariate-optimized SIA-NMR-UV method was successfully applied to several more case samples and the cathinones were definitively identified. Display omitted •Sequential Injection Analysis (SIA) was successfully hyphenated to benchtop proton NMR.•An on-line solid-phase extraction (SPE) method was developed for cathinone isolation.•Method selectivity using a broad range of interferences was investigated.•Authentic forensic case samples were studied and cathinones were definitively determined.•Multivariate optimization was performed to improve the method selectivity and sensitivity.