Comparing one's body against the bodies of others is related to lower positive body image and higher eating pathology. Underlying mechanisms as well as protective factors of these relationships are yet to be discovered. The present study examined body image flexibility and body appreciation as potential mediators of the association between appearance comparisons and eating disorder psychopathology. Additionally, it was tested whether self-compassion moderates the mediation effects. In an online sample comprising 250 women (M = 42.66, SD = 12.24), the inverse relationship between appearance comparisons and body appreciation was mediated by body image flexibility and the positive relationship between appearance comparisons and eating disorder psychopathology was mediated by body image flexibility and serially mediated by body image flexibility and body appreciation, when controlling for body mass index and age. Simple mediations were further moderated by self-compassion, such that indirect effects were attenuated at high levels of self-compassion. Promoting body image flexibility may be one potential target for helping women to engage in less maladaptive and more adaptive ways of treating the body when comparing one's appearance. Building self-compassion may be another potential target that may protect body image flexibility and its correlates in the face of appearance comparisons.