This study quantifies the relationships between innovation activity and the outcomes of business-to-consumer (B2C), business-to-business (B2B), and business-to-government (B2G) e-commerce by companies and the economic development of EU member countries. The relationship of e-commerce with innovation activities and the economic development of countries was evaluated. The analysis input was represented by annual data from the EU from 2013 to 2021, and the indicators of the e-commerce companies (where B2C, B2B, and B2G represent one variable) were classified according to company size. Twelve e-commerce indicators were analyzed in total. The panel regression analysis confirmed that a higher rate of innovation is associated with a higher rate of e-commerce, which, in turn, is associated with a higher rate of economic development in countries. Most of the relationships explored were confirmed. Nevertheless, when specifying them, it is necessary to consider the specifics of B2C and B2B with B2G. The the cluster analysis demonstrated that Bulgaria and Romania are among the countries that should pay more attention to this issue.