•We report two distinct neural mechanisms for persistence through adversity
•Perceiving control over setbacks increases persistence
•Striatum activity relates to persisting after setbacks by correcting mistakes
•Ventromedial prefrontal activity mediates effects of negative affect on persistence
How do people cope with setbacks and persist with their goals? We examine how perceiving control over setbacks alters neural processing in ways that increase persistence through adversity. For example, a student might retake a class if initial failure was due to controllable factors (e.g., studying) but give up if failure was uncontrollable (e.g., unfair exam questions). Participants persisted more when they perceived control over setbacks, and when they experienced increased negative affect to setbacks. Consistent with previous observations involving negative outcomes, ventral striatum and ventromedial prefrontal (VMPFC) activity was decreased in response to setbacks. Critically, these structures represented distinct neural mechanisms for persistence through adversity. Ventral striatum signal change to controllable setbacks correlated with greater persistence, whereas VMPFC signal change to uncontrollable setbacks mediated the relationship between increased negative affect and persistence. Taken together, the findings highlight how people process setbacks and adapt their behavior for future goal pursuit.