Objective To investigate the efficacy of adjuvant chemotherapy for patients with duodenal adenocarcinoma (DAC) at different stages. Methods A retrospective analysis was performed on patients diagnosed with DAC between January 2000 and December 2021 using data from the SEER database. Kaplan-Meier curves were utilized to evaluate the impact of adjuvant chemotherapy on survival outcomes in DAC patients with different stages. Univariate and multivariate COX regression analyses were performed to determine whether adjuvant chemotherapy served as an independent prognostic factor for cancer-specific survival (CSS) and overall survival (OS). Results A total of 1 195 patients meeting the inclusion criteria were included in the study. Of these, 620 patients (51.9%) received adjuvant chemotherapy after surgery were defined as the adjuvant chemotherapy group, whereas 575 patients (48.1%) underwent surgery alone were defined as the other group. After propensity score matching, 634 patients were retained for subsequent analysis. Subgroup analysis demonstrated that there were statistically significant differences in CSS and OS between the adjuvant chemotherapy group and other group for stage ⅢA and ⅢB patients (P < 0.05), while no statistically significant differences in CSS and OS between the adjuvant chemotherapy group and other group for stageⅠ, stageⅡA, stage ⅡB patients (P > 0.05). Multivariate analysis identified adjuvant chemotherapy as an independent protective factor for both CSS and OS in DAC patients. Additionally, age, year of diagnosis, tumor grade, number of regional lymph nodes examined (RNE), and TNM stage were identified as independent protective or risk factors for CSS and OS (all P < 0.05). Conclusions Based on substage stratification, the survival benefits of adjuvant chemotherapy for DAC patients are as follows: patients with stage ⅢA and ⅢB benefit in both CSS and OS, while patients with stage Ⅰ, Ⅱ A, and ⅡB do not benefit in either CSS or OS.