Durum wheat cultivation in Mediterranean regions is threatened by abiotic factors, mainly related to the effects of climate change, and biotic factors such as the leaf rust disease. This situation requires an in-depth knowledge of how predicted elevated temperatures and [CO2] will affect durum wheat-leaf rust interactions. Therefore, we have characterised the response of one susceptible and two resistant durum wheat accessions against leaf rust under different environments in greenhouse assays, simulating the predicted conditions of elevated temperature and [CO2] in the far future period of 2070–2099 for the wheat growing region of Cordoba, Spain. Interestingly, high temperature alone or in combination with high [CO2] did not alter the external appearance of the rust lesions. However, through macro and microscopic evaluation, we found some host physiological and molecular responses to infection that would quantitatively reduce not only pustule formation and subsequent infection cycles of this pathogen, but also the host photosynthetic area under these predicted weather conditions, mainly expressed in the susceptible accession. Moreover, our results suggest that durum wheat responses to infection are mainly driven by temperature, being considered the most hampering abiotic stress. In contrast, leaf rust infection was greatly reduced when these weather conditions were also conducted during the inoculation process, resembling the effects of possible heat waves not only in disease development, but also in fungal germination and penetration success. Considering this lack of knowledge in plant-pathogen interactions combined with abiotic stresses, the present study is, to the best of our knowledge, the first to include the effects of the expected diurnal variation of maximum temperature and continuous elevated [CO2] in the durum wheat-leaf rust pathosystem.