The present study was designed to investigate the effects of ketamine on lipopolysaccharide (LPS)-induced depressive-like behavior and the expression of inflammatory cytokines in the rat prefrontal cortex. Thirty male Wistar rats were randomly divided into 3 groups (n=10): saline group (S group), LPS only group (L group) and LPS plus ketamine group (LK group). A forced swimming test (FST) was performed. On the first day, rats were placed into water for 15 min. Twenty-four hours later, rats were treated again as in the first test for a 5 min session, and the immobility time was recorded. The prefrontal cortex was harvested for the determination of the interleukin (IL)‑1β, IL-6 and IL-10 levels. Compared with the S group, rats in the L group had significantly increased immobility time in the FST and expression of IL-1β and IL-6, and significantly decreased expression of IL-10 in the prefrontal cortex (P<0.05). However, rats in the LK group had significantly decreased immobility times in the FST and expression of IL-1β and IL-6, and significantly increased expression of IL-10 in the prefrontal cortex compared with the L group (P<0.05). Ketamine can alleviate LPS-induced depressive-like behavior, and its effect is likely associated with changes in the expression of inflammatory cytokines in the rat prefrontal cortex.