Quinoa is a high-nutrition crop originating from the Andes Mountains that is tolerant to cold, drought and salt. However, the mechanism of the high-temperature response in quinoa is still unclear. In this study, quinoa line YL-6 was used to analyze the changes in photosynthetic parameters, physiological parameters and the transcriptome after 0, 3, 12 and 24 h of heat stress. Our results showed that photosynthetic parameters, including the maximum quantum yield of PSII (Fv/Fm), steady-state effective quantum yield (ΦPSII_Lss), non-photochemical quenching (NPQ_Lss), and photochemical quenching coefficients (qL_Lss, qP_Lss), decreased significantly under heat stress, whereas the activities of antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), increased significantly at the early stage. The contents of osmotic adjustment substances such as proline, soluble protein and soluble sugar showed a non-single change trend. WGCNA was conducted to group the differentially expressed genes (DEGs) into 12 co-expression modules. Key modules associated with heat perception and signal transduction were identified, and a core regulatory network was subsequently constructed. Hub genes encoding molecular chaperones and transcription factors were screened, among which heat shock proteins (HSPs) were the most prominent. These results could provide a theoretical basis for analyzing the regulatory network of heat stress, exploring heat-resistant genes and introducing and domesticating quinoa.