The global rollout of 5G networks has raised questions regarding the potential biological effects of millimeter-wave exposure, particularly in the skin due to its limited penetration depth. This study examined the effects of whole-body exposure to 27.5 GHz millimeter waves, a frequency within the 5G FR2 bands, on skin-related biological responses in early life mice. Patched1- heterozygous knockout and wild-type CD1 mice were exposed from birth to weaning (P21), 23 h per day, in 10-minute ON/5-minute OFF cycles, at two power densities (6.67 and 20 W/m²). SHAM-exposed animals served as a control. No overt histological abnormalities were observed in exposed skin. However, molecular analyses revealed significant modulation of inflammation-related gene expression. Notably, Ccl4, Csf2, and Tnfsf11 emerged as central regulatory nodes, displaying high degree and betweenness centrality across all groups, irrespective of genotype and sex. Crucially, exposure significantly stimulated mast cell degranulation and, in wild-type mice, led to a reduction in cutaneous glutamate levels. Concurrently, a down-regulation of transcripts associated with cutaneous sensory components (Calca, Mrgprd) was observed within the skin microenvironment. These findings show that 27.5 GHz exposure induces coordinated changes in cutaneous inflammatory pathways and mast cell-mediated homeostasis without detectable structural damage. Overall, these results demonstrate a localized molecular and cellular response within the cutaneous microenvironment, reflecting a subtle homeostatic shift, and suggest that genetic background may contribute to variability in the biological response to millimeter-wave exposure.