In this study, the DIA proteomics technique was used to identify the protein expression in gastric adenocarcinoma and the corresponding paraneoplastic tissues, providing a rich gastric cancer protein expression dataset. Progranulin (PGRN), cyclin-dependent kinase 1 (CDK1), and occludin were selected for experimental validation in tissues and cell lines, of which PGRN has been shown to be involved in the development of cervical, rectal, bladder, bile duct, and breast cancer through various mechanisms. However, studies on the role of PGRN in gastric cancer are lacking. We investigated the function and mechanism of PGRN in gastric cancer using qRT-PCR, cell transfection, cell viability assays, cell scratch and Transwell assays, Western blot, and the establishment of a mouse tumor-bearing model in conjunction with bioinformatics and an analysis of the relationship between PGRN expression and the clinical and pathological characteristics and confirmed a high expression of PGRN in gastric cancer tissues. PGRN is also associated with gastric cancer prognosis, the degree of tumor differentiation, and lymph node metastasis. The inhibition of PGRN expression reduces cell viability, migration, and invasion, and the related genes and proteins changed accordingly. In the mouse tumor-bearing model, the tumor-forming ability of the subcutaneously transplanted tumors in nude mice was reduced after the inhibition of PGRN expression, and the genes and proteins associated with cell proliferation, migration, and invasion changed accordingly, thus confirming that PGRN promotes the invasiveness and metastasis of gastric cancer. An in-depth functional analysis of PGRN was performed using bioinformatics to predict protein interactions, miRNA regulation, and relationships with multiple immune cell types. An enrichment analysis revealed an involvement in multiple signaling pathways, and the MAPK signaling pathway was selected for validation. When PGRN expression was inhibited in the AGS and HGC27 cells, the expression of phosphorylated p38 (p-p38) in the MAPK pathway was increased, suggesting that PGRN may be involved in the development of gastric cancer by regulating p-P38 in the MAPK pathway. This study determined that there were differences in protein expression between gastric adenocarcinoma tissues and paraneoplastic tissues, and PGRN was a major differentially expressed protein involved in the proliferation, migration, and invasion of gastric cancer, indicating that it could be a potential new target gene for gastric cancer.