Aspergillus fumigatus is a fungal pathogen which represents a serious threat to global human health, causing over 400,000 cases of invasive aspergillosis per annum. The natural product celastrol isolated from plants is a physiologically active compound which can be used to treat a wide variety of conditions. In this study we show the antifungal properties of celastrol against A. fumigatus under both metal-deplete and replete conditions. Celastrol growth inhibition is augmented by co-addition of compound ADL2022, which decreases the inhibitory concentration of celastrol from > 100 µM to ~ 10 µM in iron-replete conditions. The combination of 0.005% (w/v) ADL2022 and celastrol in both iron and zinc-deplete and replete liquid cultures increases the observed inhibitory effect compared to celastrol alone. Celastrol treatment also alters the production and secretion of iron-scavenging siderophores, increasing the level of fusarinine C and decreasing the amount of triacetylfusarinine C produced, in a concentration dependent manner. Label-free quantitative proteomics reveals molecular insights into the effect of celastrol on the fungus showing that celastrol, and not ADL2022, is the active agent causing alterations to protein abundances and influencing growth. Co-addition of 10 µM celastrol and ADL2022 compared to ADL2022 alone for 3 h reveals an altered abundance of 94 proteins. 3 h incubation with 10 µM celastrol and ADL2022 together compared to celastrol alone alters the abundance of 7 proteins. Several enzymes from the ergosterol biosynthetic pathway are uniquely abundant in the combined treatment compared to ADL2022 alone. Generally, DNA/RNA processing proteins and membrane-domain proteins are most influenced by treatment with celastrol and ADL2022 compared to either component alone. The antifungal properties of celastrol and ADL2022 offer a potential alternative treatment strategy for A. fumigatus infections.