The mitogen-activated protein kinase p38 mediates cellular responses to injurious stress and immune signaling. Among the many p38 isoforms, p38α is the most widely expressed in adult tissues and can be targeted by various pharmacological inhibitors. Here we investigated how p38α activation is linked to cell type–specific outputs in mouse models of cutaneous inflammation. We found that both myeloid and epithelial p38α elicit inflammatory responses, yet p38α signaling in each cell type served distinct inflammatory functions and varied depending on the mode of skin irritation. In addition, myeloid p38α limited acute inflammation via activation of anti-inflammatory gene expression dependent on mitogen- and stress-activated kinases. Our results suggest a dual function for p38α in the regulation of inflammation and show mixed potential for its inhibition as a therapeutic strategy.