BACKGROUND: There is no standard chemotherapy available for unresectable or metastatic small bowel adenocarcinoma (SBA) because of its rarity. This systematic review aims to assess the efficacy and safety of chemotherapy for patients with unresectable or metastatic SBA. METHODS: In accordance with the PRISMA statements, literature search was conducted using PubMed, Scopus, and the Cochrane Central Register of Controlled Trials. The included studies were prospective randomized, nonrandomized, or observational studies. Risk of bias was assessed the ROBINS-I tool. RESULTS: Seven prospective single-arm Phase II studies were included in this review. Six of them were assessed as having a moderate risk of bias and one as having a serious risk of bias. A meta-analysis was not performed, because the studies were single-arm. Systemic chemotherapy based on fluoropyrimidine regimens achieved favorable outcomes with acceptable adverse effects as a first therapy; however, the regimens differed in each study. The object response rate was 18-50%, and the disease control rate was 29-87%. With 5-fluorouracil, adriamycin, and mitomycin-C regimen, one treatment-related death occurred. A second line of therapy including chemotherapy with nab-paclitaxel also showed favorable efficacy. The object response rate was 20%, and the disease control rate was 50%. CONCLUSIONS: Systemic chemotherapy based on fluoropyrimidine regimens was mainly used for unresectable or metastatic SBA. While it may achieve favorable outcomes with acceptable adverse effects, further evidence is needed.