The perinatal environment can be crucial for programming long‐term physiology, including the mechanisms regulating body weight, and postnatal overfeeding can lead to obesity throughout life. Inflammation‐related complications are of particular concern in the obese. However, little is known about how postnatal overfeeding contributes to changes in the ability to respond to inflammation. In the present study, we investigate changes in the febrile and neurochemical response to immune challenge with lipopolysaccharide (LPS), in juvenile and adult, male and female Wistar rats made obese by overfeeding during the postnatal period. We demonstrate that febrile responses to LPS are exacerbated in these rats, with peak core temperatures being up to 0.5 °C higher compared to those in controls, and this is associated with an enhanced pro‐inflammatory cytokine profile and enhanced hypothalamic‐pituitary‐adrenal (HPA) axis activation. Plasma pro‐inflammatory cytokines concentrations were approximately three‐fold greater in neonatally overfed rats after LPS and there were approximately twice as many neurones activated in the paraventricular nucleus of the hypothalamus as in controls, with a prolonged corticosterone response. We also observed elevated expression of toll‐like receptors (TLR) 2 and 4 in adipose tissue and greater inhibitory factor κB phosphorylation in these obese animals. Despite similar changes in expression of adipose TLR3, there was no corresponding alteration in the response to a viral mimetic that acts at this receptor. We suggest that an elevated febrile response to LPS therefore occurs in cases of obesity and this is associated with altered HPA axis function and enhanced TLR2/4 expression in adipose tissue and an up‐regulated downstream pro‐inflammatory cascade.