This research aims to develop cognitive conflict-based interactive multimedia that is valid, practical, and effective in improving students’ 21st-century skills, known as 4C skills. The development used the Plomp model, with 3 stages: preliminary research, prototyping/development phase, and assessment phase. In preliminary research, teacher questionnaires were used to discover school problems. In the development phase, interactive multimedia prototypes were designed as solutions. At this stage, a validity test was also carried out on the prototype through an expert review by 5 validators. Practicality tests were also carried out through one-to-one and small-group evaluations of 12 students. The instrument of validity and practicality sheets was used at this stage. Experimental research carried out the effectiveness test in the assessment phase 2 sample classes comprising 56 high school students. The 4C skill observation sheet instrument (critical thinking, creativity and innovation, collaboration, and communication) was used at this stage. The data were analyzed by percentage techniques, V-Aiken, N-Gain, and Mann-Whitney tests. The preliminary research results obtained some problems, including low 4C skills, teacher-centered dominant learning, and minimal use of electronic learning media. Interactive multimedia prototypes were designed as solutions. The prototype validity test results were obtained with valid categories. The results of the practicality test at the one-to-one stage and the small group stage obtained scores of 99.2 and 99.4, respectively which are in the very practical category. The results of the effectiveness test based on the N-Gain value inform the improvement of critical thinking skills, and creative thinking is in the high category, while communication and collaboration skills are in the moderate category. Based on the Mann-Whitney U test on all four skills, Sig. (2-tailed) < 0.05 was obtained, which showed a significant effect. In conclusion, cognitive conflict-based interactive multimedia can effectively improve students' 4C skills.