Background: Adolescence and early adulthood are vulnerable periods for substance use-related disorders later in life. The use of internet-enabled interventions can be useful, especially in low-resource settings. Aims: To examine the feasibility, acceptability and preliminary effectiveness of single-session digital screening and brief intervention (d-SBI) for illicit drug misuse in college students and explore barriers and facilitators of d-SBI. Methods: Design: Mixed-methods, pilot cluster randomized trial. Setting: Four conveniently selected colleges were randomized into intervention and control groups. Participants: 219 students were screened and 37 fulfilled eligibility. Twenty-four completed follow-ups. In-depth interviews were done with ten students. Intervention and Comparator: Following a digital screening, Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) based brief intervention was provided in the d-SBI group. The control group received brief education. Measurements: Acceptability was assessed by direct questions and usage statistics. ASSIST scores of groups were assessed at baseline and 3 months. Inductive coding of the interview transcript was done. Results: More than 50 % of participants found d-SBI user-friendly, appropriate and useful. Eighty percent of users, who logged in, completed screening. Per-protocol analysis showed a reduction in cannabis-ASSIST score over 3 months. The mean ASSIST score for other drugs combined did not differ significantly between groups. The difference in risk transition (moderate to low) was not significant. Qualitative analysis revealed three overarching themes- recruitment, engagement and behavior change. Conclusions: Digital SBI for drug misuse is feasible among college students. d-SBI might be effective in reducing cannabis use. © 2023 Elsevier B.V.