Excipients are used as vehicles for topical treatments; however, there are not many studies that evaluate the impact of different excipients themselves. The aim of this research is to assess skin homeostasis changes in healthy individuals after using water/oil (W/O), oil/water (O/W), Beeler base, foam and Vaseline excipients. A within-person randomized trial was conducted that included healthy individuals without previous skin diseases. Skin barrier function parameters, including stratum corneum hydration (SCH), transepidermal water loss (TEWL), pH, temperature, erythema, melanin and elasticity (R0, R2, R5 and R7), were measured on the volar forearm before and after using each excipient. Sixty participants were included in the study, with a mean age of 32 years. After applying w/o excipient erythema decreased by 25 AU, (p < 0.001) and elasticity increased by 6%. After using the o/w excipient, erythema decreased by 39.36 AU (p < 0.001) and SCH increased by 6.85 AU (p = 0.009). When applying the Beeler excipient, erythema decreased by 41.23 AU (p < 0.001) and SCH increased by 15.92 AU (p < 0.001). Foam and Vaseline decreased TEWL and erythema. Excipients have a different impact on skin barrier function. Knowing the effect of excipients on the skin could help to develop new topical treatments and help specialists to choose the best excipient according to the pathology.