Spirometra mansoni can parasitize animals and humans, cause a food/water-borne parasitic zoonosis. The knowledge of the developmental process of S. mansoni is crucial for effective treatment, thus it is important to characterize differential and specific proteins and pathways associated with parasite development. Therefore, we performed a comparative proteomic analysis of the plerocercoid and adult stages using tandem mass tag-based quantitative proteomic approach. Additionally, integrated transcriptomic and proteomic analyses were conducted to fully reveal the protein expression profiles of different lifecycle stages of the tapeworm. Approximately 1166 differentially expressed proteins (DEPs) were identified in adults versus plerocercoids, of which 641 DEPs were upregulated and 525 were downregulated. Gene Ontology (GO), Clusters of Orthologous Groups of proteins (COG) and Kyoto Encyclopedia of Genes (KEGG) analyses indicated that most DEPs related to genetic information processing and metabolism of energy in adult seems to be more activated. While in the plerocercoid stage, metabolism looks more dynamic than genetic information processing. Protein-protein interaction (PPI) revealed six key proteins possible play active roles in the growth and development of S. mansoni. Finally, the combination of transcriptomic and proteomic data suggested three pathways (ubiquitin mediated proteolysis, phagosome and spliceosome) and five proteins closely related to these pathways might have significant influence in S. mansoni. The findings here not only contributed to increasing the knowledge on the protein expression profiles of S. mansoni but also provide new insights into the functional studies on the molecular mechanisms of the neglected medical tapeworm.