Transition to higher education represents a critical period marked by academic, emotional, and social challenges that can affect students’ well-being. Although social and emotional competence (SEC) and self-care practices have been identified as protective factors of well-being, there is a gap in understanding how these concepts intersect within higher education. In a two-phase mixed-methods study, we began by exploring the main challenges perceived by higher education students in adapting to university and which SEC and self-care practices they perceived as most relevant to promoting their personal and academic well-being. Building on these insights, we then investigated the mediating role of self-care practices in the relationship between students’ SEC and their well-being. In the first stage of the study, 16 higher education students (81.3% female, M = 22.19 years) participated in semi-structured interviews; additionally, 204 higher education students (77.9% female, M = 22.10 years) responded to an online survey. Qualitative findings suggested that the most significant challenges in the adaptation to university were of a social and emotional nature, related to emotional challenges, interpersonal relationships, and personal organization. To overcome these, students primarily valued intrapersonal competencies such as self-awareness and self-regulation. Participants predominantly described using personal self-care practices, focusing on psychological and emotional care. Generalized linear model-based mediation analysis sustained that both personal and academic self-care practices mediated SEC effects on students’ personal well-being. However, only academic self-care practices mediated SEC effects on their academic well-being. Self-regulation competencies had the strongest effect on students’ personal and academic well-being. This research contributes to a strengthened theoretical understanding of the interplay between higher education students’ SEC, self-care practices, and well-being, offering new empirical evidence on how these relate.