Background: Conversion therapy can improve the survival of patients with locally advanced unresectable or potentially resectable metastatic gastric adenocarcinoma. This study was conducted to evaluate the efficacy and safety of nab-paclitaxel combined with oxaliplatin and S-1 as a conversion therapy in gastric cancer. Methods: This was a single-arm, multicenter, open-label trial of patients with locally advanced unresectable or potentially resectable metastatic gastric adenocarcinoma. Eligible patients were administered nab-paclitaxel (150 mg/m², day 1), oxaliplatin (85 mg/m², day 1), and S-1 (80–120 mg/day, days 1–14) every 21 days for two or four cycles. Radiographic assessments were performed after two cycles of treatment. Subsequent treatment or surgery was decided by the investigator according to assessment results and patient's condition. The primary endpoint was R0 resection rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: From January 2020 to September 2022, 62 patients (49 males/13 females) with a median age of 58.9 years (range: 36–73) were enrolled in this study. Sixteen (25.8%) of the 62 patients had distant metastasis. The overall response rate and disease control rate of 54 patients who underwent at least one assessment were 61.1% (33/54, 95% CI: 46.9–74.1%) and 94.4% (51/54, 95% CI: 84.6–98.8%), respectively. Of the 39 patients who underwent surgery, 33 (84.6%, 95% CI: 69.5–94.1%) patients had an R0 resection, two had an R1 resection, and four had exploratory laparotomies. The pathological complete response rate was 15.4% (6/39, 95% CI: 6.4–31.2%). After a median follow-up time of 8.4 months, the 1-year PFS rate was 68.6% (95% CI: 53.4–83.8%), whereas the median PFS and OS were not reached. Seven patients died because of disease progression (5 patients who did not undergo surgery), myocardial infarction (1 patient), and electrolyte disturbance (1 patient). Treatment-related adverse events occurred in 82.3% (51/62) patients, although most events were grade 1–2. Common hematological toxicities were leukopenia (61.3%), neutropenia (54.8%), anemia (41.9%), and thrombocytopenia (30.6%). Common non-hematological treatment-related adverse events were nausea (53.2%), fatigue (43.5%), hepatic function abnormal (33.9%), neurotoxicity (29.0%), and diarrhea (24.2%). Conclusions:Nab-paclitaxel combined with oxaliplatin and S-1 showed promising efficacy and acceptable toxicity in patients with locally advanced unresectable or potentially resectable metastatic gastric cancer. Clinical trial information: NCT04047953.