This study focused on a critical issue facing surgeons—whether to completely resect a tumor. Urinary analysis can reveal early alterations related to physiological or pathophysiological changes. Guided by this premise, we conducted experiments to evaluate proteomic variations in urine from tumor-bearing and tumor-resected mouse models. We established the tumor-bearing model using MC38 colon cancer cells in mice, categorizing them into control, tumor-resected, and tumor-bearing groups. Urine samples were collected at 7 and 30 days post resection. We employed liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) for urine proteome identification, followed by analysis for differentially expressed proteins and their functional annotations. The main findings are as follows: (1) At 7 days following tumor resection, 20 differentially expressed proteins differentiated the tumor-resected group from the tumor-bearing group. Identified biological processes included circadian rhythm regulation, Notch signaling, leukocyte cell adhesion, and heterophilic cell adhesion mediated by plasma membrane molecules. (2) At 30 days post-resection, we identified 33 differentially expressed proteins that distinguished the tumor-resected group from the tumor-bearing group, with biological processes including cell adhesion, alternative complement activation, immune system processes, and angiogenesis. (3) The proteomic differences in urine between the tumor-resected group and the healthy control group diminished at 30 days post resection. This outcome suggests that urinary proteomic changes can signal successful complete resection of MC38 tumors.