As the body’s largest organ, the skin has been surprisingly overlooked in space research. Extended space travels will strongly depend on the skin’s ability to mitigate the effects of cosmic radiation, effectively heal after physical trauma, and regulate fluid diffusion. We analyzed RNA-sequencing data from mouse dorsal skin samples from NASA’s Rodent Research 6 (RR-6) mission, focusing on transcriptomics. We found that the gene COL5A3, which codes for collagen, is up-regulated in spaceflight. Furthermore, we observed that the top overrepresented gene ontology categories were fibrillar collagen trimer, banded collagen fibril, collagen type V trimer, and structural molecule activity, which are all related to collagen or the structure of the dermis. Additionally, it has previously been reported that there is an increase in procollagen to collagen turnover, reduction in dermal strength, and increased dermal permeability in dorsal skin samples from mice exposed to microgravity. From this data, we hypothesize that the upregulation of Col5a3 in spaceflight and the alteration of genes involved in collagen assembly could contribute to decreased mechanical strength and increased permeability of the skin. Successful space travel to the Moon and especially Mars will rely on a better understanding of the effects of microgravity on the skin. Whether the changes in collagen expression observed in mice are on a whole pathogenic, beneficial, or insignificant are still inconclusive. Our findings on the increase in COL5A3 and other collagen related genes are notable and merit future validation studies using biochemical and histological analyses.