Background: To explore the efficacy and safety of neoadjuvant intraperitoneal and systemic (NIPS) paclitaxel chemotherapy combined with apatinib and S-1 in the treatment of gastric cancer patients with positive exfoliative cytology. Methods: Patients with gastric cancer (P0CY1) who were confirmed to have free cancer cells (FCCs) in the abdominal cavity after laparoscopic exploration from April 2018 to August 2019 were enrolled. All patients underwent NIPS chemotherapy using paclitaxel combined with apatinib and S-1 treatment. Laparoscopic exploration was performed after 3 cycles of conversion therapy. The primary study endpoint was the FCC negative rate, and the secondary study endpoints were overall survival time (OS), progression-free survival time (PFS), objective response rate (ORR), disease control rate (DCR), and safety indicators. Results: Out of 312 advanced gastric cancer patients who underwent laparoscopic exploration, 36 patients with P0CY1 gastric cancer were identified and enrolled in this study. After 3 cycles of conversion therapy, the ORR was 80.56% and the DCR was 94.44%. All patients underwent secondary laparoscopic exploration, and the FCC conversion rate was 77.78%. All patients with negative FCC underwent R0 surgical resection, with a median follow-up time of 11.4 months. The median survival time was 15.5 months, and the 1-year OS was 80.55%. The median PFS was 14.4 months, and the 1-year PFS was 75.00%. Treatment-related grade 3 adverse reactions were mainly leukopenia and neutropenia. No grade 4 adverse reactions were observed. There were no reported deaths related to chemotherapy or surgery in the study cohort. Conclusions: NIPS with paclitaxel combined with apatinib and S-1 treatment may increase the FCC negative rate of P0CY1 gastric cancer patients.