This paper reports on a study investigating the use of gamification as a teaching strategy in an online setting for developing upper-secondary students' 21st century skills (i.e., collaboration, critical reasoning, communication, solving complex problems, and being able to use and manage digital tools and devices). More specifically, the study aimed to empirically explore pedagogical design perspectives as well as students' and teachers' experiences on what opportunities and challenges they perceive about gamification teaching designs in this context. University students co-created the gamification activities' design and the participating teachers chose virology and immunology (Biology 2 for upper-secondary schools in Sweden) as the topics. The study was conducted during Spring 2020 and in total 26 upper-secondary students, 2 teachers, and 7 engineering students studying in the Master of Science programmes participated. The empirical material is based on observations during the online tests in which the school students tested the university students' design, a survey with the school students, postinterviews with the teachers and the university students, and the university students' written report as a mandatory assignment in their course. The findings illustrate three themes: 1) developing pedagogical design principles for online gamification activities, 2) the school students' experiences, and 3) the participating teachers' experiences. The findings show that designing for gamification teaching in an online setting with a specific purpose in developing students' 21st skills is quite a complex process. The participating teachers, for example, perceive gamification teaching designs as a catalyst for motivating and engaging students' learning to a high extent, but the challenges they experience concern foremost how to design tasks and assess an individual student's knowledge in collaborative assignments. The collaboration between the university and K–12 education concerned combining the different competences in the TPACK-model, and in addition aligning expressed motives and goals towards an applied teaching design. This presented study is an aspiration and a practical example of directing towards development of smart learning ecosystems.