Background Adverse mental health effects have been reported following oil spills but few studies have identified specific responsible attributes of the clean-up experience. We aimed to analyse the effects of the 2010 Deepwater Horizon (Gulf of Mexico) disaster on the mental health of individuals involved in oil spill response and clean-up. Methods We used data from the Gulf Long-term Follow-up Study, a cohort of workers and volunteers involved in oil spill clean-up after the Deepwater Horizon disaster. We included 8968 workers (hired after completing training for oil spill response and clean-up) and 2225 non-workers (completed training but were not hired) who completed a Patient Health Questionnaire-8 and four-item Primary Care PTSD Screen to assess for probable depression and post-traumatic stress disorder (PTSD) indicators. Participants were recruited between March 28, 2011, and March 29, 2013. The mental health indicators were assessed at home visits done between May 12, 2011, and May 15, 2013. We used regression models to analyse the effect of potentially stressful job experiences, job type, and total hydrocarbon exposure on mental health indicators. Findings Oil spill response and clean-up work was associated with increased prevalence of depression (prevalence ratio [PR] 1·22, 95% CI 1·08–1·37) and PTSD (PR 1·35, 95% CI 1·07–1·71). Among workers, individuals who reported smelling oil, dispersants, or cleaning chemicals had an elevated prevalence of depression (1·56, 1·37–1·78) and PTSD (2·25, 1·71–2·96). Stopping work because of the heat was also associated with depression (1·37, 1·23–1·53) and PTSD (1·41, 1·15–1·74), as was working as a commercial fisherman before the spill (1·38, 1·21–1·57; and 2·01, 1·58–2·55, respectively). An increase in exposure to total hydrocarbons appeared to be associated with depression and PTSD, but after taking into account oil spill job experiences, only the association between the highest amount of total hydrocarbons and PTSD remained (1·75, 1·11–2·76). Interpretation Oil spill clean-up workers with high amounts of total hydrocarbon exposure or potentially stressful job experiences had an increased prevalence of depression and PTSD. These findings provide evidence that response and clean-up work is associated with adverse psychological effects and suggest the need for mental health services both before and after the event. Funding National Institutes of Health (NIH) Common Fund and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences.