Abstract: Objective To observe the clinical efficacy and adverse reactions of amilorotinib hydrochloride combined with chemotherapy versus chemotherapy alone in the first-line treatment of patients with advanced pancreatic cancer. Methods A total of 71 patients with advanced pancreatic cancer who were treated in the Affiliated Hospital of Xuzhou Medical University from May 2020 to May 2023 were included. They were divided into two groups: a test group and a control group. The test group received amilorotinib hydrochloride combined with albumin- bound paclitaxel/gemcitabine, while the control group was administered with albumin- bound paclitaxel/gemcitabine. Both groups were compared for clinical efficacy and adverse reactions. Results The disease control rate of the test group was 76.47%, which was significantly higher than that of the control group (54.05%, P＜0.05). The objective remission rate was 32.35% for the test group, and 24.32% for the control group, without statistical differences (P>0.05). The test group presented improvement in median progression-free survival time, overall survival time, and 1-year survival rate, compared with the control group (P＞0.05). In terms of adverse reactions, most of treatment-related adverse reactions in the two groups were grades 1 and 2, which were tolerable. The test group presented higher incidences of hypertension, proteinuria, gingival and oral swelling, hand-foot syndrome, and diarrhea than the control group (P<0.05), but most of them were grades 1 and 2. Conclusions The first-line treatment of advanced pancreatic cancer with amlotinib hydrochloride combined with albumin-bound paclitaxel/gemcitabine is superior to chemotherapy alone in terms of efficacy, with tolerable adverse reactions, which is worthy of further clinical promotion.