Abstract Purpose Adverse drug reaction (ADR) underreporting is highly prevalent across the world. This study aimed to identify factors associated with ADR reporting and map these to a behavioural change framework to help inform future interventions designed to improve ADR underreporting. Methods A mixed methods survey was distributed to healthcare professionals at a tertiary hospital in Sydney, Australia. Quantitative data was analysed using logistic regression to identify factors that predict ADR reporting. Qualitative data was evaluated using content analysis. These were then integrated and mapped to the 14 domains within the Theoretical Domains Framework (TDF) to identify target areas relevant for improving ADR reporting. Results One hundred thirty-three healthcare professionals completed the survey. Knowing how to report ADRs (OR 4.56, 95%CI 1.95–10.7), having been trained on ADR reporting (OR 2.72, 95%CI 1.29–5.77), and encountering ADRs as part of clinical practice (OR 10.3, 95%CI 3.59–29.4) were significant predictors of reporting an ADR. Content analysis identified three categories: modifying the ADR reporting process, enabling clinicians to report ADRs, and creating a positive ADR reporting culture. After data integration, the three target TDF domains were knowledge, environmental context/resources, and beliefs about consequences. Conclusion Future interventions designed to improve ADR reporting should address these target domains to instigate behaviour change in healthcare professionals’ reporting of ADRs.