School innovativeness has become a crucial criterion for the long-term success of education systems in terms of their adaptability to societal changes. We examined the relations among school innovativeness—measured by teachers’ perceptions to what extent the climate at their school is open for innovation and change—and key outcomes at the teacher and school level, including contextual effects. Large-scale data from the 48 countries participating in the Teaching and Learning International Survey (TALIS) 2018 (N = 154,959) were utilized. To quantify effects and explain possible between-country variation, we performed multilevel structural equation modeling and meta-analyses. The data supported the hypothesis that more innovative schools delivered better outcomes in terms of teacher collaboration and exchange, job satisfaction, cognitive activation of students, and innovative teaching practices. The strength of relations varied by outcome and country. Contextual effects of school innovativeness existed for job satisfaction, teaching practices, and exchange among teachers. The data revealed that effects involving teacher collaboration and exchange as well as job satisfaction were more homogeneous across countries than those involving cognitive activation and innovative teaching practices. As hypothesized, teachers’ prior opportunities-to-learn how to teach cross-curricular skills, how to use information and communication technology (ICT), and how to handle diversity were directly related to the outcomes and indirectly via school innovativeness, thus confirming a mediating role of the latter. The data supported the hypothesis that country patterns could be explained by countries’ cultural orientation (individualism vs. collectivism), yet not their economic status. We discuss implications for educational policy making and teacher education.