Background Study: As interest in programming education continues to grow, more educators are incorporating programming into K-12 classrooms. There is evidence that programming can help develop essential skills for future societal advancement, known as 21st century skills. However, there has been limited research into which sub-skills of 21st century skills are fostered through programming and the effect sizes thereof. Objective: This study presented a meta-analysis to comprehensively understand the influence of programming instruction in K-12 classrooms on the development of students' 21st century skills in different dimensions of sub-skills. And further analysed the impact of key elements of programming instruction design on its effectiveness. Methods: A comprehensive meta-analysis was conducted, covering 74 empirical studies published between 2000 and 2023, involving 136 effect sizes, and moderation analyzes on variables of instructional design. Results: This study indicated that implementing programming instruction in K-12 schools can help develop students' multiple dimensions of 21st century skills, such as critical thinking, creativity, communication, collaboration, problem-solving and decision, learning to learn, ICT literacy, and personal and social responsibility. Overall, programming demonstrates a moderate but significant effect on improving 21st century skills (Hedges's g = 0.621, p = 0.000 < 0.01). Furthermore, several best practices were identified to enhance students' 21st century skills, including initiating programming education from kindergarten, limiting the duration of programming interventions to 6 months, adopting interdisciplinary approaches to programming education, utilizing visual programming tools, and selecting appropriate assessment methods. Conclusion: Based on these findings, this study recommended the thoughtful design of programming education to maximize its advantages in various dimensions of 21st century skills.