Research has found meditation to be associated with improved mental health; however, less is known about how these positive outcomes develop. To better understand the operant effects of meditation on mental health, this study is set forth to examine the potential mediating effects of commonly measured constructs of mindfulness and self-compassion on trait anxiety, a personality trait prevalent in many psychiatric conditions. This longitudinal study uses a meditation treatment (n = 108) and comparative control (n = 94) designed to examine relational changes in mindfulness, self-compassion, and trait anxiety data collected in three waves: (a) baseline, (b) mid-program, and (c) post-program. Structural equation modeling (SEM) revealed significant increases in mindfulness and self-compassion scores among the treatment cohort and cross-lagged regression models that revealed significant reductions in trait anxiety were mediated by preceding increases in mindfulness. SEM model testing found that increases in mindfulness precipitate increases in self-compassion, but neither self-compassion nor anxiety mediated mindfulness. Whereas both self-compassion and mindfulness were associated with reductions in anxiety, the cultivation of mindfulness had the most robust mediating effect on reductions in trait anxiety. These finding reinforce previous studies that have suggested that increases in mindfulness skills may mediate the effects of meditation on mental health outcomes. Among the strengths of the current study are the longitudinal three waves of data, including mid-program data that enables cross-lagged regression. The cross-lagged models indicate the temporal ordering of changes and reveal mindfulness as the key mediating variable preceding substantive changes in self-compassion and trait anxiety.