Abstract Skin photosensitization is a common challenge following intravenous administration of many photodynamic therapy (PDT) drugs, typically lasting days, weeks, or months in laboratory animals and patients. Symptoms of photosensitivity manifest as erythema and edema on skin exposed to sunlight or bright artificial lighting. Recent efforts using nanocarriers to increase photosensitizer accumulation in tumors have also been shown to reduce skin photosensitivity. We previously developed phototheranostic PORPHYSOME (PS) nanoparticles self‐assembled from porphyrin–lipid conjugates and capable of potent anti‐tumor PDT. Here, we demonstrate in a nonpigmented rat skin model that PS exhibit less severe and shorter‐lasting skin photosensitivity compared with an equivalent drug dose of porfimer sodium (PHO), the canonical first‐generation PDT drug. At 2, 4, 8, and 12 days post intravenous injection, depilated skin was exposed to escalating doses of simulated solar light. Light exposure 4 days post‐injection showed markedly reduced symptoms of skin photosensitivity with PS than PHO. By Day 8, the minimal dose of light eliciting any kind of skin reaction was significantly higher with PS than PHO, and by Day 12, there was no detectable skin response with PS. These differences were attributed to altered intradermal distribution and faster clearance of PS vs. PHO in rat skin.