Objective. To evaluate the clinical efficacy of laparoscopic Billroth II subtotal gastrectomy plus lienal polypeptide injection for gastric cancer. Methods. Between May 2018 and January 2021, 110 patients with gastric cancer treated in Jingzhou First People’s Hospital were recruited and assigned via the random number table method to either an observation group or a control group, with 55 patients in each group. All patients received laparoscopic Billroth II subtotal gastrectomy, and the observation group additionally received lienal polypeptide injection. Outcome measures include surgical indexes, clinical efficacy, and adverse events. Results. The patients in the observation group had significantly less intraoperative hemorrhage volume, smaller surgical wounds, shorter time lapse before passing gas and hospital stay, and longer operation time than those in the control group (
P
<
0.001
). The observation group showed significantly higher efficacy than the control group (
P
=
0.001
). The observation group had a significantly lower incidence of toxic side effects and adverse events than the control group (
P
<
0.05
). After treatment, the CD3+ and CD4+ levels were significantly elevated and the CD8+ level was decreased, with higher CD3+ and CD4+ levels and lower CD8+ levels in the observation group than in the control group (
P
<
0.05
). Conclusion. In the treatment of patients with gastric cancer, laparoscopic Billroth II subtotal gastrectomy plus lienal polypeptide injection features promising efficacy, improves the immune function of patients, effectively reduces the occurrence of toxic side effects and adverse reactions, with less trauma and rapid recovery, which shows good potential for use in clinical application.