Although some studies have examined the effects of self-regulated learning (SRL) strategies on learning effectiveness, inconsistent results have been reported. Additionally, studies that adopt the perspective of SRL to evaluate the effect of metacognitive skills on students' actual learning effectiveness in digital game-based learning (DGBL) contexts are scarce. Based on SRL theory, this study develops a research model to examine the impacts of learners' prior knowledge and metacognition on their use of cognitive strategy and learning effectiveness in DGBL environments. Additionally, this study developed a DGBL system and adopted a quasi-experimental research approach with a pretest and posttest design. Data of the experiment were collected by using a questionnaire and were then used to verify the proposed research model. Survey data from 227 research participants who were taking a course on system analysis and design were analyzed to validate the developed research model. The results reveal that prior knowledge and metacognitive skills significantly affect both cognitive strategy and learning effectiveness. Prior knowledge positively moderates the relationship between learners' metacognitive skills and cognitive strategy. Students with weak prior knowledge of DGBL are more likely to adopt a cognitive strategy that has a positive effect on learning effectiveness.