Infection with Echinococcus granulosus, a life-threatening zoonotic parasite, can remain asymptomatic for a long time; it is generally detectable only in the advanced stages, which delays treatment in most patients. Here, we aimed to determine what E. granulosus infection does to the host organs and how E. granulosus evades the host immune system and remains undetectable for a long time, and eventually understand the interactions between E. granulosus and the hosts in depth. Therefore, we established a mouse model of E. granulosus infection at the early, middle, and late stages, obtained samples from its liver (the most frequently affected host organ), and performed comparative, quantitative proteomic analyses. Our results indicated the potential changes in the host lesion proteome during the development of E. granulosus infection. They may aid in developing methods for early and effective diagnosis of cystic echinococcosis and identifying relevant core regulatory targets of parasite–host interactions.