Decisions under uncertainty distinguish between those made under risk (known probabilities) and those made under ambiguity (unknown probabilities). Despite widespread interest in decisions under uncertainty and the successful documentation that these distinct psychological constructs profoundly—and differentially—impact behavior, research has not been able to systematically converge on which brain regions are functionally involved in processing risk and ambiguity. We merge a lesion approach with computational modeling and simultaneous measurement of the arousal response to investigate the impact the medial prefrontal cortex (mPFC), lateral prefrontal cortex (lPFC), and amygdala have on decisions under uncertainty. Results reveal that the lPFC acts as a unitary system for processing uncertainty: Lesions to this region disrupted the relationship between arousal and choice, broadly increasing both risk and ambiguity seeking. In contrast, the mPFC and amygdala appeared to play no role in processing risk, and the mPFC only had a tenuous relationship with ambiguous uncertainty. Together, these findings reveal that only the lPFC plays a global role in processing the highly aversive nature of uncertainty.