Blended synchronous learning (BSL) is becoming increasingly widely implemented in many higher education institutions due to its accessibility and flexibility. However, little research has been conducted to explore students’ engagement and persistence and their possible predictors in such a learning mode. The purpose of this study was to investigate how to facilitate students’ engagement and persistence in BSL. In detail, this study used structural equation modeling to explore the relationships among specific predictors (self-regulation, teaching presence, and social presence), learning engagement, and learning persistence in BSL. We recruited 319 students who were enrolled in BSL at a Chinese university. The online survey was administered to gather data on the variables of this study. The results demonstrated that self-regulation, teaching presence, and social presence were positively associated with learning engagement. Self-regulation and learning engagement were positively associated with learning persistence. Moreover, learning engagement mediated the relationships between self-regulation, teaching presence, social presence, and learning persistence. This study suggests that self-regulation, teaching presence, and social presence are significant predictors for student learning engagement and persistence in BSL.