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The present paper treats the issue of methodological assumptions in mainstream neuropsychology and, as counter-concepts, in Vygotsky’s approach and Holzkamp’s critical psychology. The analysis identifies four main assumptions concerning the methodology of mainstream neuropsychology, which are contrasted with the positions of other approaches. The methodologies of the mainstream neuropsychology vs. Holzkamp’s and Vygotsky’s approach assume: (1) mechanistic vs. dialectical materialism; (2) formal vs. dialectical logic; (3) decomposition into elements vs. units; (4) reductionism of psychic processes to the brain vs. activity as a unity of environmental and organism-pole. Despite the vast coincidence in their main assumptions, we also discuss nuances of difference between Holzkamp’s and Vygotsky’s approaches. The former, possibly due to its reference to cultural-historical activity theory (CHAT) and its theoretical neglection of the organism-pole of psychic functions, falls short of structural considerations in its accounts on phylogenetic emergence. On the other hand, Vygotsky’s neuropsychology does not fully explore the phylogenetic emergence of basic units of functional psychic organisation. This might be due to certain implications of Vygotsky’s initial accounts, which seem to highlight cultural development to the detriment of phylogenetic one.