The epidermal barrier function is disrupted in various inflammatory skin diseases. Accurate methods to measure skin barrier function are needed to assess the effect of therapeutic agents. Therefore, we developed a noninvasive multiparametric approach to measure four different parameters regarding the skin barrier. In the current pilot study, we evaluate this method in 14 healthy volunteers. We assessed erythema, transepidermal water loss (TEWL), water content, and epidermal thickness at both cheeks before and 30 min after application of Lanette and Vaseline-Lanette cream. For this, we used spectrophotometry, the Aquaflux device, the Epsilon device, and reflection confocal microscopy, respectively. Stratum corneum (SC) thickness was significantly increased after application of both creams (p < 0.05), and this increase was larger after Lanette cream compared to after Vaseline-Lanette cream (p = 0.035). Erythema, TEWL, and water content did not significantly change after cream application. Our multiparametric approach is promising and offers a feasible and practical way to quickly obtain multifaceted information about skin barrier function. Further exploration of this approach after prolonged use of cream and in conditions of disrupted skin barrier are recommended areas for future research.