The cross-talk between hyperproliferative keratinocytes and activated immune cells is responsible for the progression of psoriasis. The strategy to alleviate psoriasis through inhibiting the abnormal proliferation of keratinocytes remains challenging due to limited therapeutic effects and low skin penetration of drugs. Herein we designed an ultrasound-triggered phase-transition nanodroplet that could produce cavitation to enhance skin penetration and effectively generate reactive oxygen species (ROS) to induce keratinocyte apoptosis for psoriasis treatment. After ultrasound stimulation, the perfluoro-n-pentane (PFP) liquid core of the nanodroplets vaporized, and the Haematoporphyrin monomethyl ether (HMME) encapsulated in the nanodroplets generated plenty of intracellular ROS which caused the apoptosis of HaCat cells through inducing mitochondrial dysfunction. In addition, the blank nanodroplets successfully inhibited the secretion of IL-6 and TNF-α from macrophages and dendritic cells in vitro due to the anti-inflammatory effect of POPG. For the skin penetration test, the phase-transition nanodroplets could effectively accumulate in the epidermis of the skin and generate intracellular ROS. The in-vivo anti-psoriasis experiment demonstrated that the phase-transition nanodroplets relieved the symptoms of psoriasis lesion and inhibited epidermal hyperplasia through induction of cell apoptosis under ultrasound irritation. Meanwhile, the inflammatory cytokines in the skin lesion almost decreased to the normal baseline level after SDT. Collectively, this study demonstrated a new strategy to inhibit keratinocyte hyperproliferation for psoriasis management based on sonodynamic responded nanodroplets.