On the earth, the majority of cellular functions are regulated by mechanical loads. The effects of cell response to mechanical loads under microgravity on the adaptive changes of physiological functions in space cannot be ignored. The cytoskeleton is widely considered as one of the key structures through which cells sense gravity variation and respond to mechanical loads. In this review, the research progress on the changes and mechanisms of the ‘ cytoskeleton-LINC complex-nuclear lamina’ pathway in cellular mechanoperception and mechanotransmission under microgravity is summarized, and the future research is prospected.