This work is focused on the development and evaluation of completely natural anti-aging creams, with the aid of the experimental design. Model formulations, differing in the content of emollients (10%/15%/20%) and emulsifier (1%/2%/3%) and containing the Acmella oleracea extract as a model anti-aging active were prepared by the cold process and evaluated regarding rheological behavior (con-tinuous rotational and oscillatory tests) and physical stability (dynamic-mechanical thermoanalysis-DMTA test). To study the influence of varied formulation parameters and their interaction on the critical rheological characteristics of the developed creams, a D-optimal design within the response surface method was applied. The data acquired from rheological characterization revealed favorized pseudoplastic (shear-thinning) flow behavior with the yield point, and dominating elastic behavior (storage modulus G' > loss modulus G") in both, amplitude and frequency sweeps, which together with a rather small and constant structural change obtained in the DMTA test indicated satisfying overall physical stability of formulated creams. The results of D-optimal design showed a significant individual, as well as a mutual effect of the tested formulation factors (emollient concentration, emulsifier concentration) affecting critical quality attributes (apparent viscosity, yield point, flow point, G', G", structural change) of developed anti-aging creams. Based on optimization results, the model formulation containing 20% of the emollient mixture and 2% of the emulsifier was selected as preferred in terms of required rheological properties and, thus, desired stability and quality, and it could be considered as a promising candidate worth exploring further for efficacy and in vivo skin performances.