Synthetic cathinones continue to proliferate in clandestine drug markets worldwide. N‐ethylnorpentylone (also known as N‐ethylpentylone or ephylone) is a popular emergent cathinone, yet little information is available about its toxicology and pharmacology. Here we characterize the analytical quantification, clinical presentation, and pharmacological mechanism of action for N‐ethylnorpentylone. Liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) was used to quantify N‐ethylnorpentylone in blood obtained from human cases. Clinical features exhibited by the intoxicated individuals are described. The activity of N‐ethylnorpentylone at plasma membrane transporters for dopamine (DAT), norepinephrine (NET) and 5‐HT (SERT) was assessed using in vitro assays measuring uptake inhibition and evoked release of [3H] neurotransmitters in rat brain synaptosomes. Our LC–MS/MS method assayed N‐ethylnorpentylone concentrations with limits of detection and quantification of 1 and 5 ng/mL, respectively. Quantitation was linear from 5 to 500 ng/mL, and the method displayed specificity and reproducibility. Circulating concentrations of N‐ethylnorpentylone ranged from 7 to 170 ng/mL in clinical cases, and the associated symptoms included palpitations, tachycardia, agitation, hallucinations, coma and death. N‐Ethylnorpentylone was a potent inhibitor at DAT (IC 50 = 37 nM), NET (IC 50 = 105 nM) and SERT (IC 50 = 383 nM) but displayed no transporter releasing activity. We present a validated method for quantifying N‐ethylnorpentylone in human case work. The drug is a psychomotor stimulant capable of inducing serious cardiovascular and neurological side‐effects which can be fatal. In vitro findings indicate that N‐ethylnorpentylone exerts its effects by potent blockade of DAT and NET, thereby elevating extracellular levels of dopamine and norepinephrine in the brain and periphery.