Exposure of neonatal animals to anesthetics may cause developmental functional changes and acute structural anomalies in the brain. Clonidine, an α2-adrenoceptor agonist, functions as an analgesic and sedative and protects against brain injury. Nevertheless, whether clonidine protects the developing brain from damage caused by sevoflurane (SEVO) anesthesia remains unclear. Seven-day-old rats were exposed to 3% SEVO for 6 h, during which time either clonidine or saline was injected three times. The arterial blood gases, respiratory rate, and anesthesia level of each rat were evaluated. Western blot analysis was employed to detect proinflammatory cytokines, NF-κB, and cleaved-caspase-3. Surgical anesthesia was adequately induced by SEVO. No rats died during the study. Compared with untreated rats, SEVO induced production of cleaved-caspase-3. Administration of clonidine and SEVO significantly reduced apoptosis. Moreover, nuclear translocation and NF-κB phosphorylation were inhibited by clonidine, and interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) production decreased after SEVO administration. Marked apoptosis in the brain was induced by SEVO anesthesia. Clonidine treatment provided significant protection against SEVO-induced apoptosis.