The growing specialization and formalization of economic knowledge threatens to break away from the general scientific base that forms the worldview of the researcher. An urgent task is presented in the reintegration of basic methodological principles and categories of science into modern social science and economic theory. The article conducts a comparative analysis of the works of K. Marx and K. Popper, who made revolutionary changes in the methodology and ideological attitudes (conceptual frameworks) of scientific knowledge. Marx’s contribution focuses on dialectical and historical materialism, the doctrine of the economic basis of society and the change of socio-economic formations; Popper’s contribution focuses on his trial and error method with falsifying interpretation of results and the concept of successive three worlds of the universe. Popper’s criticisms of Marxist doctrine (essentialism, elements of mythology, teleologism) and the counterarguments of consistent Marxists are evaluated. The paper characterizes Popper’s positions on the realism of scientific knowledge, the world of predispositions, flexible management in animate and inanimate nature, the world of mental states of consciousness and the world of the objective content of thinking. Their commonality with the provisions of dialectical and historical materialism (the material nature of objective reality, the theory of reflection, the role of objective mental forms and ideological social relations) in the formation of the ‘world of objective knowledge’ is shown. The insufficiency of Popper’s epistemology for the study of the economic basis of social life is revealed. Based on a structural and logical analysis of the methodological principles and theoretical positions of Marx and Popper, the paper outlines the paths to the development of a system of concepts that brings together the complementary results of their apparently opposing research programs. Also presented are sources showing the relevance of the ideas of Marx and Popper in modern methodological and socio-economic literature. It is concluded that the world of objective knowledge (the key category of Popper’s social science) is part of the socio-economic life of society (in its Marxist interpretation), which, in turn, is incomplete without taking into account the realities of this world and needs additional study from the appropriate angle.