To elaborate the decisive role of surfactants in promotion of aceclofenac’ skin absorption, potentially avoiding irritation, we developed non-ionic microemulsions varying natural or synthetic surfactants: sucrose esters (laurate or myristate) vs. polysorbate 80. A comprehensive physicochemical characterization indicated no significant influence of the solubilized nonsteroidal anti-inflammatory drug on the bicontinuous structure of blank formulations. To evaluate skin tolerability of isopropyl alcohol, a sucrose ester-based microemulsion containing transcutol P as a cosurfactant was also developed. The measured skin parameters strongly depended on the (co)surfactant type, showing higher compatibility of the microemulsions containing sucrose ester and isopropyl alcohol. In vitro release results, in vivo tape stripping and pharmacokinetics in rats confirmed superiority of the sucrose ester- over polysorbate-based microemulsions (total amounts of aceclofenac penetrated 60.81 ± 5.97 and 60.86 ± 3.67 vs. 27.00 ± 5.09 μg/cm2, and its maximum plasma concentrations 275.57 ± 109.49 and 281.31 ± 76.76 vs. 150.23 ± 69.74 ng/ml for sucrose laurate- and myristate- vs. polysorbate 80-based microemulsions, respectively). Hence, sugar-based excipients increased delivery of aceclofenac through stratum corneum by increasing its fluidity, showing overall more satisfying safety profiles. In conclusion, sucrose ester-based microemulsions proved to be promising carriers for dermal/transdermal aceclofenac delivery.