Ghrelin has exhibited potent anti-inflammatory effects on various inflammatory diseases. The aim of this study was to investigate the potential effects of ghrelin on a model of ventilator-induced lung injury (VILI) established in rats. Male Sprague-Dawley rats were randomly divided into three groups: low volume ventilation (LV, Vt = 8 ml/kg) group, a VILI group (Vt = 30 ml/kg), and a VILI group pretreated with ghrelin (GH + VILI). For the LV group, for the VILI and GH + VILI groups, the same parameters were applied except the tidal volume was increased to 40 ml/kg. After 4 h of MV, blood gas, lung elastance, and levels of inflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and (MIP)-2 and total protein in bronchoalveolar lavage fluid (BALF) were analyzed. Myeloperoxidase (MPO), (TLR)-4, and NF-κB, were detected in lung tissues. Water content (wet-to-dry ratio) and lung morphology were also evaluated. The VILI group had a higher acute lung injury (ALI) score, wet weight to dry ratio, MPO activity, and concentrations of inflammatory mediators (TNF-α, IL-6, IL-1β, and MIP-2) in BALF, as well as higher levels of TLR4 and NF-κB expression than the LV group (P < 0.05). All histopathologic ALI, the inflammatory profile, and pulmonary dynamics have been improved by ghrelin pretreatment (P < 0.05). Ghrelin pretreatment also decreased TLR4 expression and NF-κB activity compared with the VILI group (P < 0.05). Ghrelin pretreatment attenuated VILI in rats by reducing MV-induced pulmonary inflammation and might represent a novel therapeutic candidate for protection against VILI.