The proposed paper deals with the innovation, innovation activities, and innovation performance in Visegrad countries (e.g., Czech Republic, Poland, Hungary, and Slovak Republic). Three of these countries are classified as the high-income countries and one as the upper middle-income country. The analysis is based on the global innovation index (GII) of both the input and output side indexes by the OECD and EUROSTAT data. The changes of indexes by the Visegrad countries are identified as well as the trends. The contribution discusses differences or distances between the indexes and their stability. The comparison of global innovation index in Visegrad countries shows the opportunities for better understanding of the innovation activity conditions as well as the performances in the innovation in the country. Two of Visegrad countries are ranked better by innovation output (IO) indexes and two by innovation input (II) indexes. All these countries are weak in market sophistication. It is the opportunity for non-technological innovation processes. This is also the challenge of optimizing the institutional systems and processes. In the context of innovation, the key challenge is developing skills for innovation in education and training systems and connected with the changes and expenditures on education and training. The aim is to connect the equipment of more people with the skills related to innovation and creativity in all its forms. All countries have to increase the outputs based on the knowledge, innovation, and creativity.