Androgenetic alopecia (AGA) is a chronic and progressive form of hair loss characterized by vascular degeneration in the perifollicular microenvironment, leading to cell apoptosis and eventual loss of hair follicles (HFs). Traditional therapeutic formulations, such as Minoxidil (MXD) tincture, have limitations in reshaping the perifollicular microenvironment and exhibit limited effectiveness. Here, we report a multi-synergistic therapeutic platform for high-performance hair regeneration therapy. The platform combines microneedle (MN) patches loaded with MXD-encapsulated nanostructured lipid carriers (MXD-NLC-MNs) and cold atmospheric plasma (CAP). The MNs’ mechanical strength enables efficient transdermal delivery of MXD to the targeted dermal papilla cells, promoting cell proliferation. Furthermore, in collaboration with MXD, the mechanical stimulation exerted by MN application synergistically upregulates the expression of vascular endothelial growth factor, leading to neoangiogenesis. Meanwhile, the transient microchannels in the skin created by MNs facilitate the transdermal delivery of CAP-generated nitric oxide (NO) to the sites of HF lesions, whereby the synergistic interaction between MXD and NO boosts perifollicular vasodilation. Consequently, the perifollicular microenvironment can be effectively reshaped to accelerate hair regeneration in AGA murine models. This multi-synergistic combination therapy strategy would hold great promise for effectively treating AGA and promoting hair regrowth.