Background. Sufentanil is widely used during anesthesia induction. However, it can cause coughing via different mechanisms. This study is aimed at evaluating the effectiveness of a small dose of oxycodone and sufentanil in suppressing sufentanil-induced cough (SIC) during general anesthesia induction. Methods. Of the 174 patients scheduled for elective surgery, 144 were eligible and 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 the anesthesia induction. Their 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, patients from 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 significantly reduced compared with 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. Preconditioning using intravenous oxycodone (0.02 mg/kg) or sufentanil (0.02 μg/kg) could represent an effective approach to reducing SIC in anesthesia induction and was associated with relatively stable hemodynamic state during general anesthesia. This trial is registered at Chinese Clinical Trial Registry with registration number ChiCTR1900021087.