Popcorn disease, a fungal infection is reportedly known to affect the production of mulberry, however, there is no known research data available regarding the effects of popcorn infected leaves on silkworm performance. One group of silkworms was fed infected mulberry leaves and the second silkworms group was given control mulberry leaves that were infection free. Results showed that infected leaves exhibited limited toxicity to the silkworm; however, the cocoons yield found in infected group was deeply affected. Compared with control group, the biggest body weight, cocoon weigh, cocoon shell weight, pupal weight in infected group was 9.3%, 8.8%, 11.4% and 10.2%, respectively, lower than that of control group. Although the groups obtain a similar group oviposition, group good oviposition and group oviposition rate (P>0.05), the single oviposition, single good oviposition and single oviposition rate were significantly reduced by infected leaves. Furthermore, to elucidate the molecular resistance mechanism of fruit mulberry “Da10” i.e., popcorn disease, Two-dimensional electrophoresis (2-DE), matrix-assisted laser desorption/ ionisation time-of-flight tandem mass spectrometry (MALDI-TOF-TOF MS) and bioinformatics technique were used for characterize the differential expressed proteins. Almost 78 patho-stress responsive proteins which expression level more than 1.5-fold were identified, where 50 proteins were up-regulated and 28 proteins were down-regulated; The identified proteins were categorized into 16 classes, which are mainly including energy metabolism, gene expression regulation, oxidation-reduction reaction, cellular component and stress responses, and the stress proteins including Mn-superoxide dismutase and thaumatin-like protein. The results means that mulberry young fruits can regulate the expression levels of multiple proteins to reply popcorn disease and these pathogenesis-related proteins provide valuable information to further study the pathogenesis of popcorn disease and disease-resistant molecular breeding in mulberry.