This study examined (a) the effects of professional development (PD) intervention on third- to fifth-grade teachers' knowledge and skills of teaching practice for multilingual learners (MLs), and (b) the relationship between teachers' enhanced knowledge and skills, MLs' self-efficacy in learning, and MLs' academic performance. The sample consisted of 21 treatment teachers and 22 control teachers, as well as 210 treatment MLs and 220 control MLs. A multilevel linear regression analysis was performed. The findings show that treatment teachers had a higher level of knowledge and skills in teaching practice for MLs than control teachers ([gamma hat] = 1.3 and 1.15, respectively). Furthermore, treatment MLs had a higher level of self-efficacy in learning and higher academic performance than control MLs ([gamma hat] = 0.41 and 0.58, respectively). Additionally, teachers' knowledge and skills of teaching practice for MLs significantly predicted MLs' self-efficacy in learning ([gamma hat] = 0.15 and 0.14, respectively). Also, MLs' self-efficacy in learning played a significant role in predicting their academic performance ([gamma hat] = 0.49). These findings indicate that MLs' self-efficacy mediates the relationship between: (a) teachers' knowledge of teaching practice and MLs' academic performance, and (b) teachers' skills of teaching practice and MLs' academic performance.