Interictal epileptiform discharges (IEDs) are brief, sporadic, pathologic electrical bursts in the brains of patients with epilepsy. IEDs represent an important disease biomarker for tracking seizure risk and they also convey direct pathophysiological impacts including on cognitive function. While most work in human IED mechanisms has targeted the population-level neural activity using macro-electrode recordings, the single-neuron mechanisms of IEDs across the depth of human cortical lamina in vivo are largely unknown. We leveraged high-density Neuropixels probes to evaluate single-neuron activity across 9 cortical columns during 6 recording sessions while patients with epilepsy underwent awake brain surgery. We identified IEDs from the concurrent local-field potential (LFP) and discovered three consistent neuronal firing patterns to which they were time-locked. Neurons with a rapid-onset firing pattern tightly aligned with IED maximal slopes encoded IED waveform amplitude. These rapid-onset neurons localized most often to deeper cortical layers while the other two peri-IED neuronal firing-patterns were widely distributed across cortical lamina. Leveraging the instantaneous firing patterns across multiple neurons, an IED could be predicted up to 750 ms before maximal slope. Across all IED-locked neurons, the majority were also coherent to low-frequency LFP oscillations and, crucially, two-thirds were modulated by behavior during language tasks. Together, these results demonstrate the distinct neuronal-laminar substrates of human IEDs and provide mechanistic links to cognitive impairment, by which IEDs co-opt physiological circuits.