Summary Dendritic cells (DCs) are critical antigen‐presenting cells which are the initiators and regulators of the immune response. Numerous studies support the idea that dietary sugars influence DC functions. Increased consumption of fructose has been thought to be the leading cause of metabolic disorders. Although evidence supports their association with immune dysfunction, the specific mechanisms are not well understood. Fructose is one of the main dietary sugars in our diet. Therefore, here we compared the effect of fructose and glucose on the functions of human DCs. High levels of D‐fructose compared to D‐glucose led to activation of DCs in vitro by promoting interleukin (IL)‐6 and IL‐1β production. Moreover, fructose exposed DCs also induced interferon (IFN)‐γ secretion from T cells. Proinflammatory response of DCs in high fructose environment was found to be independent of the major known metabolic regulators or glycolytic control. Instead, DC activation on acute exposure to fructose was via activation of receptor for advanced glycation end product (RAGE) in response to increased accumulation of advanced glycation end products (AGE). However, chronic exposure of DCs to high fructose environment induced a shift towards glycolysis compared to glucose cultured DCs. Further investigations revealed that the AGEs formed by fructose induced increased levels of inflammatory cytokines in DCs compared to AGEs from glucose. In summary, understanding the link between metabolic changes and fructose‐induced DC activation compared to glucose has broad implications for immune dysfunction associated with metabolic disorders. High fructose is more inflammatory and induces different metabolic changes in DCs than high glucose. Fructose induces inflammation in DCs via the activation of RAGE–AGE pathway. The study provides evidence for immune dysfunction associated with various metabolic disorders.