Salmonella infection poses a serious threat to the poultry industry, causing significant economic losses. Under global warming conditions, the underlying molecular mechanisms by which heat stress affects bacterial infections in poultry remain unclear. This study conducted a Salmonella Typhimurium infection under heat stress in Guang Ming broilers. A total of 100 chickens were randomly divided into three groups: control group (CTL), Salmonella Typhimurium (ST) infection group, and heat stress and Salmonella Typhimurium (HS + ST) co-stimulation group. By integrating inflammatory phenotypes, liver transcriptome profiles, and weighted gene co-expression network analysis (WGCNA), we systematically investigated the key regulatory factors through which heat stress affects host susceptibility to Salmonella. The results demonstrated that heat stress reduced body weight gain, exacerbated Salmonella Typhimurium-induced inflammatory responses, and increased mortality. Transcriptome results revealed that heat stress led to excessive inflammatory responses and antioxidant defense imbalances. Combined differential expression analysis and WGCNA identified three hub regulatory genes: PTGDS and WISP2 showed significant correlations with the heterophil/lymphocyte ratio, while SLC6A9 was significantly correlated with serum IL-8 levels. Validation in HD11 cell infection models confirmed the differential expression of these genes under heat stress and Salmonella Typhimurium co-stimulation, indicating their critical roles in host immune regulation. This study elucidates the intrinsic regulatory relationships through which heat stress promotes Salmonella pathogenicity and inflammatory responses, providing important insights for disease-resistant poultry breeding and prevention strategies.