This study aimed to investigate the effect of a nurse-led multidomain intervention on chemotherapy induced nausea and vomiting (CINV) in patients with head and neck squamous cell carcinomas (HNSCC). Ninety-two HNSCC patients who received cisplatin-based chemotherapy were divided into intervention group (n = 45) and control group (n = 47). The control group received usual care of CINV, which consisted of administration of antiemetics according to physicians' preference, education about CINV control and dietary recommendations provided by primary nurses. The intervention group received nurse-led, evidence-based multidomain management, including nurse-led CINV risk factors assessment, education on prevention and control of CINV, antiemetics following guidelines, dietary strategies, and relaxation therapy. The number of patients who experienced CINV was collected. The severity of CINV was graded according to the Common Terminology Criteria for Adverse Events v3.0. The influence of CINV on patient's quality of life was assessed by the Functional Living Index-Emesis (FLIE). The incidence and the severity of nausea and vomiting in the intervention group were significantly lower than those in the control group within 5 days after chemotherapy, and the scores of the dimension of nausea and vomiting in the intervention group were significantly higher than those in the control group 63.00 (50.00–63.00) vs 40.00(28.00–63.00), 63.00(63.00–63.00) vs 63.00 (43.00–63.00), the differences were statistically significant (P < 0.05). Nurse-led multidomain intervention can reduce the incidence and the severity of CINV in patients with HNSCC who were treated with cisplatin-based chemotherapy, and thus reduced the influence of CINV on patients' quality of life. NCT05792228. •This study developed a nurse-led multidomain intervention for the patients' chemotherapy-induced nausea and vomiting (CINV) management.•The intervention combined pharmacologic and nonpharmacologic therapies and provided optimized strategies given the evidence based approach.•These strategies reduced the incidence and severity of CINV and improved patients' quality of life, indicating good management practices.