Abstract: Background and Objective: Climate change related heat and nutritional stress weakens the animal’s immune system and makes them more prone to diseases. Although this has been observed by various researchers, the impact of these stresses on immune gene expression and process of heat stress mediated immune suppression at molecular level has not been dealt in detail in goat. Hence, the study was conducted to establish the impact of heat stress, nutritional stress and combined stresses (heat and nutritional) on different spleen Toll Like Receptor (TLR) genes expression in Osmanabadi goats. Materials and Methods: Twenty four adult Osmanabadi male goats (average body weight 16.0 kg) were divided into four groups viz., C (n = 6, control), HS (n = 6, heat stress), NS (n = 6, nutritional stress) and CS (n = 6, combined stress). The study was conducted for a period of 45 days. The C and HS goats had ad libitum access to their feed while NS and CS goats were under restricted feed (30% intake of C bucks) to induce nutritional stress. The HS and CS goats were exposed to heat stress in outside environment for 6 h a day between 10:00-16:00 h to induce heat stress. The average minimum and maximum temperature and Relative Humidity (RH) during the study period were 27.23±3.46, 38.33±0.52 and 37.0±4.16, respectively. The animals were slaughtered and their spleen was collected for different TLR mRNA expression. The relative gene expression was calculated using the formula 2–ΔΔCT. The results were expressed in fold change as compared to untreated control (control = 1 fold). Results: The fold expression level of TLR 1, 2, 3, 6, 7, 8, 9 and 10 mRNA in spleen followed the same trend in the current study where comparatively higher expression was noticed in CS group. These different TLR mRNA expressions in CS group were of higher magnitude as compared to both HS and NS group goats. This shows the severity of environmental stresses when occurring simultaneously and the consequences on immune response were much more severe than the individual stress. Conclusion: The activated splenic innate immune functions in terms of different increased TLR expression during combined stress indicate the Osmanabadi goat’s adaptation and disease resistance mechanism under extreme environmental conditions.