Aim: Postoperative cognitive dysfunction (POCD) is a common complication after surgery that can have a long-lasting negative impact on the patient’s quality of life. Although the underlying mechanism is still unknown, evidence suggests that neuroinflammation may play an important role. Here we aimed to confirm the presence of neuroinflammation in a rat model of POCD and investigated the impact of the surgical procedure on brain metabolism. Nutrition is believed to affect cognition and brain metabolism and could modulate neuroinflammation. We therefore also evaluated the impact of a multi-nutrient supplementation diet containing anti-inflammatory ingredients on surgery-induced biochemical alterations in the brain and on POCD symptoms. Materials and Methods: POCD after major abdominal surgery in humans was mimicked in rats by exteriorizing the gastrointestinal tract and clamping the mesenteric artery for 30 min. To assess the validity of the model, behavioral changes were evaluated in the first postoperative week. The effects of surgery on neuroinflammation and brain glucose metabolism were monitored noninvasively by positron emission tomography (PET) and postmortem by immunohistochemistry. To assess the effect of nutrition, rats were fed a control diet or investigational diet starting either 2 weeks before or immediately after the surgical intervention. Results: Major surgery caused significant bodyweight loss, reduced exploratory behavior, increased anxiety and tended to decrease spatial memory. [11C]PK11195-PET imaging and immunohistochemistry confirmed the presence of neuroinflammation in several brain regions after surgery. [18F]FDG-PET imaging revealed both increased and decreased brain metabolism in distinct parts of the brain. Dietary intervention started prior to surgery had a positive impact on recovery, resulting in faster gain in bodyweight and normalization of exploratory behavior and spatial memory. This improvement was accompanied by a reversal of astrocyte activation in the periventricular zone and a normalization of brain metabolism in part of the motor cortex. Dietary intervention started after surgery reversed astrocyte activation in cerebellum and the periventricular zone and decreased brain metabolism in the piriform cortex, but had no beneficial effect on anxiety and spatial memory. Conclusion: This study shows that major surgery can be accompanied by neuroinflammation and changes in glucose metabolism in several brain regions. Preventive intervention with a diet containing anti-inflammatory nutrients can affect neuroinflammation and brain metabolism and has a positive effect on the recovery from abdominal surgery in rats. These results indicate that a dietary intervention can have an effect on brain physiology and warrant further investigation of this concept.