Digital game-based learning has shown usefulness in developing EFL vocabulary knowledge and encouraging learner application of self-regulated learning (SRL) strategies. Previous literature revealed that applying SRL strategies might improve motivation. High motivation, in turn, may promote vocabulary knowledge development - These findings may be generalised in digital game-based learning and explain its effectiveness. However, so far, motivation and its associated interplay have barely been considered in this learning context. To address the gap, we developed a self-regulated digital game-based EFL vocabulary learning (SR-DGBVL) program and conducted mixed-method research on motivation, application of SRL strategies, vocabulary knowledge development, and their interplay therein. One-hundred-and-one Chinese university students (experimental group: 50; control group: 51) engaged in our study and were evaluated through pre-test, immediate post-test, and delayed post-test of vocabulary knowledge, questionnaires, and semi-structured interviews. Results revealed that the SR-DGBVL participants experienced significantly greater improvements in vocabulary knowledge and reported higher levels of motivation compared to those in the conventional vocabulary learning context. We also found motivation to be a full mediator between the use of SRL strategies and vocabulary knowledge development. Interestingly, the application of SRL strategies appeared consistent across different learning methods. From these findings, we suggest long-term SRL training, investigation of SRL strategies with consideration of motivational variables, and longitudinal qualitative studies on learners' SRL strategy use.