Mindfulness practices form the core of numerous therapeutic programs and interventions for stress reduction and the treatment of different health conditions related to stress and life habits. Ways and means to regulate oneself effectively also form the foundation of the path of yoga in the accomplishment of holistic health and well-being. The self-awareness, self-regulation, and self-transcendence (S-ART) model can be considered as an overarching neurobiological framework to explain the self-regulatory mechanisms of well-being present in mindfulness-based practices. The current study, by connecting and applying the S-ART framework to the self-regulatory mechanisms in yoga and generating related hypotheses, provides a theory-led explanation of the action of yoga practices, which is sparse in the literature. Testing the S-ART model in yoga in two culturally diverse samples, assessing the model-mapped psychological mechanisms of action, and exploring the influence of perseverance in yoga practice are the original contributions of this study. The study sample comprised 362 yoga practitioners and non-practitioners (197 Indian and 165 Spanish), who completed four tests of psychological variables indicative of the aforementioned three S-ART abilities. These tests were Multidimensional Assessment of Interoceptive Awareness (MAIA), Experiences Questionnaire-Decentering (EQ-D) subscale, Difficulties in Emotion Regulation Scale (DERS), and Relational Compassion Scale (RCS). The results indicated significantly better self-awareness and self-regulatory abilities in yoga practitioners (Indian and Spanish in a combination) than non-practitioners, reflected in higher levels of interoceptive awareness and decentering abilities. Moreover, perseverance in yoga practice acted as a significant predictor of self-awareness and self-regulation in practitioners. An analysis of each cultural sample revealed some differences. Yoga practice and perseverance in it acted as a significant predictor of interoceptive awareness and decentering in Indian practitioners having more than 1 year of sustained yoga practice, but for the Spanish participants, physical exercise and frequency of yoga practice acted as better predictors of interoceptive awareness and decentering in comparison to yoga practice and perseverance in it. The obtained results suggested that the S-ART model provided preliminary but promising evidence for the self-regulatory mechanisms of action in yoga practice within a culturally diverse sample of yoga practitioners. This study also widens the scope of generating further hypotheses using the S-ART theoretical framework for testing the self-regulatory mechanisms of action in yoga practice.

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