<p>This article develops a&#xa0;model of self-regulation in work activity. Starting from the concept of meta-regulation as “higher-order regulation,” it distinguishes between automatic and controlled processes and locates their biopsychological foundations (arousal, activation, effort) within Sanders’ cognitive-energetic model. Building on this, four forms of regulation (person- vs. task-related × internal vs. external) are systematically derived and integrated into the Self-Regulation in Work Activity (SRA) model via an Activity–Control System (AKS). Empirically, we show that interindividual differences in self-regulation competence (SRK)—operationalized through the dimensions General Activation (GA) and Anxious Tension (HA) as both trait and state—are systematically related to physiological indicators (heart rate) in laboratory studies, as well as to features of work design, regulatory obstacles, resources, and leadership behavior in field studies. The findings underscore the importance of self-regulation for performance, well-being, and human-centered work design. We conclude with implications for research and practice in the context of technological change.</p><p><i>Practical Relevance</i>: The findings highlight self-regulation competence as a&#xa0;key resource for performance, well-being, and as an indicator of human-centered work design. Promoting self-regulatory abilities—through job designs that provide autonomy, task completeness, and minimal regulatory obstacles—can enhance both psychological health and work effectiveness. The presented SRA model offers a&#xa0;theoretically and empirically grounded framework to support such interventions.</p>