Objective To investigate the short-term efficacy， long-term prognosis， and safety of trastuzumab deruxtecan （T-DXd） combined with the IP chemotherapy regimen （irinotecan + cisplatin） in the treatment of HER2-positive advanced gastric cancer， as well as its effects on the serum tumor markers of patients. Methods A prospective， randomized， and controlled study design was employed to enroll 96 patients with HER2-positive advanced gastric cancer who received treatment at the hospital from August 2021 to August 2023. The patients were randomly assigned to the observation group （n = 48， treated with the T-DXd + IP chemotherapy regimen） and the control group （n = 48， treated with the trastuzumab + IP chemotherapy regimen） using the random number table method. The objective response rate （ORR）， disease control rate （DCR）， overall survival （OS）， progression-free survival （PFS）， and 2-year survival rate were compared between the two groups， and the safety of the treatment was assessed. Serum tumor markers ［carbohydrate antigen 724 （CA72-4）， carbohydrate antigen 199 （CA19-9）， carcinoembryonic antigen （CEA）， vascular endothelial growth factor （VEGF）］， serum inflammatory indicators ［monocyte chemoattractant protein-1 （MCP-1）， interleukin-1β （IL-1β）］， and immune response indicators ［soluble programmed death ligand-1 （sPD-L1）， IL-2， interferon-γ （IFN-γ）］ were measured. Results The objective response rate （ORR） of the observation group was 58.33%， which showed no significant difference compared to that of the control group （45.83%） （P > 0.05）. The disease control rate （DCR） in the observation group was 87.50%， which was higher than the 70.83% in the control group （P < 0.05）. After treatment， the levels of carcinoembryonic antigen （CEA）， carbohydrate antigen 19-9 （CA19-9）， carbohydrate antigen 72-4 （CA72-4）， vascular endothelial growth factor （VEGF）， monocyte chemoattractant protein-1 （MCP-1）， and interleukin-1β （IL-1β） in both groups decreased from the baseline levels （P < 0.05）. Moreover， the above-mentioned levels in the observation group were lower than those in the control group （P < 0.05）. The incidence rates of grade 3 or higher neutropenia and anemia in the observation group were higher than those in the control group （P < 0.05）， while there was no statistical significance in the incidence rate of cardiac toxicity between the two groups （P > 0.05）. The median progression-free survival （PFS） and median overall survival （OS） were significantly higher in the test group than those in the control group （P < 0.05）， and there were no statistical differences in the 2-year overall survival rate （P > 0.05）. Conclusion T-DXd combined with IP chemotherapy regimen improves the short-term efficacy in patients with HER2-positive advanced gastric cancer， reduces the serum levels of tumor markers， VEGF， and MCP-1， and prolongs the median PFS and OS. Although it is associated with an increased risk of hematological and gastrointestinal adverse events， the overall safety is controllable， suggesting that the combined regimen may become a new treatment option for this population.