Intolerance of uncertainty (IU) is proposed to be a transdiagnostic causal mechanism of psychological difficulties. The systematic review sought to evaluate the status of evidence pertaining to IU's proposed causal influence upon symptoms of psychological conditions. The review collated evidence from studies involving experimental manipulation and assessment of temporal precedence to ensure direct assessment of causality. The search strategy and eligibility screening identified 12 articles, detailing 15 eligible studies (experimental manipulations: n = 10; temporal precedence studies: n = 5). Available evidence comprised symptoms of anxiety-and mood-related conditions, including obsessive-compulsive disorder (OCD). The greatest support for IU as a causal mechanism was evident for anxiety-related difficulties and, to a lesser extent, negative affect; limited support was found for OCD-related difficulties. However, notable inconsistency across study findings for all difficulty types precludes absolute conclusions. Implications and recommendations are discussed.