Background: Nivolumab plus chemotherapy (Nivo-Chemo) is the standard treatment for advanced gastric cancer based on the results of CheckMate 649 trial and ATTRACTION-4 trial. However, real-world data on the efficacy of Nivo-Chemo are limited. This study aimed to assess the efficacy of Nivo-Chemo in the clinical practice setting by comparing it to chemotherapy alone. Methods: We retrospectively reviewed the medical records of patients with advanced gastric cancer who received palliative chemotherapy in our hospital between 2017 and 2023. The inclusion criteria were as follows: age ≥ 20 years; histologically confirmed advanced unresectable or recurrent gastric/gastro-esophageal junction adenocarcinoma; HER2 negative or unknown; and no prior treatment. Patients were divided into two groups based on their first-line treatment: the Nivo-Chemo group and chemotherapy alone (Chemo) group. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) were assessed. Results: Of 78 patients, 52 patients were in the Chemo group and 26 patients were in the Nivo-Chemo group. Median age were 69 years (range 30–83) and 67 years (range 39–76) in the Chemo group and Nivo-Chemo group. Eastern Cooperative Oncology Group performance status (ECOG PS) was 0/1/2 in 18/27/7 patients (35%/52%/13%) in the Chemo group and in 17/8/1 patients (65%/31%/4%) in the Nivo-Chemo group. Histological type (Intestinal type/diffuse type) was 19/33 (37%/63%) in the Chemo group and 8/18 (31%/69%) in the Nivo-Chemo group. Combined positive score (CPS) was assessed in 21 patients in the Nivo-Chemo group. The CPS <1/1-5/>5 was in 3/10/8 (12%/38%/31%). In the Chemo group, 28 patients (54%) received anti-PD-1 monotherapy after progression of first-line chemotherapy. The median PFS was 5.7 months in the Chemo group and 6.0 months in the Nivo-Chemo group (HR 0.88, 95% CI 0.50-1.55, p = 0.66). The median OS was 15.0 months in the Chemo group and 18.6 months in the Nivo-Chemo group (HR 0.76, 95% CI 0.37-1.53, p = 0.44). The ORR was 50% in the Chemo group and 54% in the Nivo-Chemo group, while the DCR was 63% and 69%, respectively. Conclusions: In clinical practice, the addition of nivolumab to chemotherapy tended to provide a survival benefit compared to chemotherapy alone.