Introduction Opioid prescribing has increased 15-fold in Australia in the past two decades, alongside increases in a range of opioid-related harms such as opioid dependence and overdose. However, despite concerns about increasing opioid use, extramedical use and harms, there is a lack of population-level evidence about the drivers of long-term prescribed opioid use, dependence, overdose and other harms. Methods and analysis We will form a cohort of all adult residents in New South Wales (NSW), Australia, who initiated prescribed opioids from 2002 using Pharmaceutical Benefits Scheme dispensing records. This cohort will be linked to a wide range of other datasets containing information on sociodemographic and clinical characteristics, health service use and adverse outcomes (eg, opioid dependence and non-fatal and fatal overdose). Analyses will initially examine patterns and predictors of prescribed opioid use and then apply regression and survival analysis to quantify the risks and risk factors of adverse outcomes associated with prescribed opioid use. Ethics and dissemination This study has received full ethical approval from the Australian Institute of Health and Welfare Ethics Committee, the NSW Population and Health Services Research Committee and the ACT Health Human Research Ethics Committee. This will be the largest postmarketing surveillance study of prescribed opioids undertaken in Australia, linking exposure and outcomes and examining risk factors for adverse outcomes of prescribed opioids. As such, this work has important translational promise, with direct relevance to regulatory authorities and agencies worldwide. Project findings will be disseminated at scientific conferences and in peer-reviewed journals. We will also conduct targeted dissemination with policy makers, professional bodies and peak bodies in the pain, medicine and addiction fields through stakeholder workshops and advisory groups. Results will be reported in accordance with the REporting of studies Conducted using Observational Routinely collected Data (RECORD) Statement.