Cognitive inflexibility is theorized to be an etiological and maintenance factor for self-injurious thoughts and behaviors (SITBs). The vast literature on cognitive flexibility and SITB is rife with conflicting results, and thus, is challenging to interpret. We conducted a systematic review to synthesize the available evidence on cognitive flexibility and SITB (n = 126 studies). Results indicate most laboratory paradigms we reviewed have poor ecological validity, and many studies use inadequate measures of cognitive flexibility. Evidence suggests cognitive flexibility, as currently measured, is not robustly associated with SITB history above and beyond certain psychopathology presentations (e.g., depression). Cognitive reappraisal appears to be more cognitively demanding for persons with (vs. without) suicidal ideation (SI) and/or nonsuicidal self-injury history. Higher cognitive flexibility may have a distal protective influence on SITB by buffering the effects of perceived stress and psychological pain. Preliminary evidence indicates that state cognitive flexibility may have a proximal association with concurrent state SI. Nonetheless, cognitive flexibility does not appear to be a primary mechanism of change in many SITB interventions, however, further research is warranted. We discuss several notable limitations in the current literature and make suggestions to guide future research in this area.