Background: Sufentanil is widely used during anesthesia induction. However, sufentanil injections can cause cough through different mechanisms. This study aimed to evaluate the effectiveness of a small dose of oxycodone and sufentanil in suppressing sufentanil-induced cough (SIC) during general anesthesia induction.Methods: This prospective, randomized, controlled trial was conducted form February 12, 2019 to December 30, 2019. A total of 174 patients were scheduled for elective surgery, and 144 screened patients were randomly divided into 3 groups (n=48). Five minutes before sufentanil bolus (0.4 μg/kg), patients in group O received 0.02 mg/kg oxycodone intravenously within 5 s, those in group S received 0.02 μg/kg sufentanil within 5 s and those in group N received an equal volume of 0.9% normal saline within 5 s. Sufentanil was diluted to 5 μg/ml and administered within 5 s after pretreatment. The incidence and severity of cough in the three groups were evaluated within 1 minute after sufentanil injection during anesthesia induction. Mean arterial pressure (MAP) and heart rate (HR) were recorded at T0 (after entering the operation), T1 (3 minutes after pretreatment), T2 (before intubation), and T3 (1 minute after intubation).Results: The incidences of cough in group N, group O, and group S were 20 (41.6%), 7 (14.5%), and 6 (12.5%), respectively. Compared with group N, group O and group S exhibited significantly reduced incidence and severity of cough, and the severity of cough in group O and group S was dramatically reduced compared with that in group N (P<0.05). No significant differences in the rangeability of MAP and HR were noted at the four time points in the three groups (P> 0.05).Conclusion: Intravenous oxycodone (0.02 mg/kg) and sufentanil (0.02 μg/kg) represent effective approaches to reducing SIC in anesthesia induction and ensuring a relatively stable hemodynamic state during general anesthesia induction.Trial registration: Chinese Clinical Trial Registry (ChiCTR1900021087, registered date: January 28, 2019), http://www.chictr.org.cn