Given early childhood is a critical period for acquiring the twenty-first-century skills, the present study aimed to examine the effect of design-oriented STEM activities on the twenty-first-century skills of preschool children in line with the experimental design. A mixed factorial analysis of variance (ANOVA) of 3 (time: pre-test, post-test and persistence) × 2 (experimental group and control group) was used to test the hypothesis. The Bayesian factor analysis for mixed data was performed to identify the effects of design-oriented STEM education on differences between groups as well as within the group. The study results indicated that design-oriented STEM activities permanently increased the total scores of the children in the experimental group as regards the twenty-first-century skills. It also appeared that design-oriented STEM activities permanently enhanced all sub-dimensions of life and career skills; learning and innovation skills; and information, media and technology skills. In the end, a number of recommendations were presented in accordance with the results of the study.