Fusarium crown rot (FCR) is a soil-borne disease that causes significant economic and yield losses in cereal-growing regions worldwide. Although the association between FCR development and drought stress has been recognized, the molecular mechanisms connecting these two stresses remain poorly understood. In this study, we employed label-free quantitative proteomic analysis to investigate the protein expression patterns of wheat plants under FCR, drought, and combined stress conditions. Our findings revealed significant negative interactions between FCR and drought stress during the reproductive stages. The combined stress of FCR and drought had a more detrimental effect on wheat growth compared to each stress condition alone. We identified a total of 823, 414, and 1520 differentially expressed proteins (DEPs) in response to FCR, drought, and the combined stress, respectively. Many unique and shared DEPs, as well as gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with the three stress conditions. Notably, certain proteins, such as chitinase and glutathione S-transferase (GST), were found to be shared among all three stress conditions, suggesting their critical roles in FCR resistance under drought stress. This study provides valuable insights into the complex interactions between FCR and drought at the proteomics level, thereby facilitating future efforts at genetic improvement of FCR resistance in wheat.