Traditionally associated with Th17-mediated pathways, palmoplantar pustulosis (PPP) is a persistent inflammatory dermatosis limited to the palms and soles. However, therapeutic responses to IL-17/IL-23 suppression are often limited, indicating significant immunological heterogeneity. There is growing evidence that type 2-associated immunological pathways may have a role in the persistence of disease in some patients. Herein, we report a 40-year-old woman with refractory PPP who had no personal or familial history of psoriasis or atopy. She was treated with stapokibart, an IL-4Rα monoclonal antibody that inhibits IL-4/IL-13 signaling, and experienced a rapid and long-lasting remission. Previous treatments, such as topical corticosteroids, retinoids, and Tripterygium wilfordii, were ineffective. Lesional skin exhibited moderate phosphorylated STAT6 positivity in scattered inflammatory infiltrates, independent of CD4+ T-cell presence, indicating engagement of canonical IL-4/IL-13 signaling at the tissue level, despite normal serum IgE levels and the lack of peripheral or tissue eosinophilia. The context-dependent clinical significance of Th2 pathway regulation in PPP is highlighted by a systematic literature review combined with our case. In non-atopic individuals, who frequently have noticeable pruritus despite unimpressive systemic atopic indicators, blockade of IL-4/IL-13 signaling has resulted in significant clinical relief. On the other hand, it has also been observed that blocking Th2-related pathways, such as IL-4/IL-13, IL-5, or IL-31, paradoxically causes PPP, highlighting the bidirectional and context-dependent significance of Th2 signaling in disease pathogenesis. Together with clinical characteristics like excessive pruritus, tissue-level Th2 activation may offer useful indicators to direct precision treatment in this diverse illness.