Electroconvulsive therapy (ECT) is a fast-acting, highly effective, and safe treatment for medication-resistant depression. Historically, the clinical benefits of ECT have been attributed to generating a controlled seizure; however, the underlying neurobiology is understudied and remains largely unresolved. Using optical neuroimaging to probe neural activity and hemodynamics in a mouse model of ECT, we demonstrated that a second brain event follows seizure: cortical spreading depolarization (CSD). We further found that ECT stimulation pulse parameters and electrode configuration directly shaped the wave dynamics of seizure and subsequent CSD. To translate these findings to human patients, we tested for the presence of hemodynamic signatures of post-ictal CSD using non-invasive diffuse optical monitoring of cerebral blood flow and oxygenation during routine ECT treatments. We found evidence that humans generate hyperemic waves after ECT seizure which are highly consistent with CSD. These results challenge a long-held assumption that seizure is the primary outcome of ECT and point to new opportunities for optimizing ECT stimulation parameters to precisely modulate brain activity and treatment outcomes.