Previous research has found that content and language integrated learning (CLIL) is an effective method to improve undergraduate students’ English reading performance. Little is known, however, about the underlying mechanisms of such this association or factors that might strengthen or weaken these processes. Therefore, based on the framework of action research, the current study aimed to fill this gap by scrutinizing the changes in and effects of academic vocabulary size (AVS), academic self-efficacy (ASE), and learning motivation (LM) on English reading performance over a 16-week semester. A total of 202 Chinese undergraduate students (majoring in English Education) participated in this study. The results revealed the following major findings: (1) students’ AVS, ASE, LM, and English reading performance were significantly improved through CLIL implementation during this semester, (2) AVS, ASE, LM, and English reading performance were positively related to each other, (3) AVS significantly predicted students’ English reading performance, (4) ASE and LM partially mediated the effect of AVS on English reading performance. These findings contribute to the understanding of the impact of CLIL on English reading performance. Limitations and implications for educational practices are discussed.