Successful vocabulary acquisition hinges on the harmonious interplay of various factors. Despite some studies that have been conducted to examine the direct effect of self-regulation on vocabulary learning, few of them tapped into the relationship among self-regulation, motivational beliefs, vocabulary learning strategies and vocabulary proficiency. This study extended previous research by examining whether motivation, self-efficacy and learning strategies mediate the relationship between self-regulation and vocabulary proficiency and investigating whether the relationship varied by gender. Data were extracted from 399 senior secondary school students. Results from structural equation modelling revealed that motivation and self-efficacy mediated the relationship between self-regulated learning capacity and vocabulary learning strategies. Vocabulary learning strategies further mediated the relationships between self-efficacy, motivation and vocabulary proficiency. Meanwhile, the relationship between self-regulation, motivational beliefs, vocabulary learning strategies and vocabulary proficiency held equivalent across genders. Theoretical and practical implications are discussed.