Background Psychological practitioners often seek to directly change the form or frequency of clients’ maladaptive perfectionist thoughts, because such thoughts predict future depression. Indirect strategies, such as self-compassion interventions, that seek to change clients’ relationships to difficult thoughts, rather than trying to change the thoughts directly could be just as effective. This study aimed to investigate whether self-compassion moderated, or weakened, the relationship between high perfectionism and high depression symptoms in both adolescence and adulthood. Methods The present study utilised anonymous self-report questionnaires to assess maladaptive perfectionism, depression, and self-compassion across two samples covering much of the lifespan. Questionnaires were administered in a high school setting for the adolescent sample (Study 1, Mage = 14.1 years, n = 541), and advertised through university and widely online to attract a convenience sample of adults (Study 2, Mage = 25.22 years, n = 515). Results Moderation analyses revealed that self-compassion reduced the strength of relationship between maladaptive perfectionism and depression in our adolescent Study 1 (β = -.15, p < .001, R2 = .021.) and our adult study 2 (β = -.14, p < .001, R2 = .020). Limitations Cross-sectional self-reported data restricts the application of causal conclusions and also relies on accurate self-awareness and willingness to respond to questionnaire openly. Conclusions The replication of this finding in two samples and across different age-appropriate measures suggests that self-compassion does moderate the link between perfectionism and depression. Self-compassion interventions may be a useful way to undermine the effects of maladaptive perfectionism, but future experimental or intervention research is needed to fully assess this important possibility.