Infantile epileptic spasms syndrome (IESS) is an age-dependent epileptic encephalopathy of the developing brain, yet its underlying mechanisms remain unclear. Monocarboxylate transporter 2 (MCT2) maintains cerebral metabolic homeostasis via energy substrate transport, but its role in IESS epileptogenesis is unknown. We found that MCT2 was predominantly expressed in neurons and downregulated in IESS patient specimens. In contrast, in human temporal lobe epilepsy (TLE) specimens, MCT2 expression showed no statistically significant difference relative to controls. We observed this downregulation of neuronal MCT2 in an IESS rat model. Transcriptomic analysis 24 h post-spasms revealed enrichment in mitochondrial pathways and oxidative phosphorylation. Consistently, the translocase of outer mitochondrial membrane 20 (TOMM20) was markedly downregulated in the cortex of IESS patients and a betamethasone/N-methyl-D-aspartate (NMDA)-induced rat model, which also displayed ultrastructural mitochondrial damage, reactive oxygen species accumulation, and an imbalanced Bax/Bcl-xL ratio. Following adeno-associated virus (AAV)-mediated MCT2 knockdown in the neonatal rat somatosensory cortex, we observed that reduced MCT2 expression significantly shortened latency to spasm onset, increased spasm frequency, and exacerbated post-spasm TOMM20 loss. These findings indicate that impaired MCT2-mediated transport may compromise mitochondrial function and lower the threshold for spasm generation, a characteristic feature of this infantile-onset epilepsy. Neuronal MCT2 thus represents a promising therapeutic target for IESS.