The microbial fermentation of plants is a promising approach for enhancing the yield of polysaccharides with increased activity. In this study, ten microbial strains, Lactiplantibacillus plantarum CCFM8661, Limosilactobacillus reuteri CCFM8631, Lactobacillus helveticus M10, Lacticaseibacillus rhamnosus CCFM237, Lactilactobacillus sakei GD17-9, Lacticaseibacillus casei CCFM1073, Bacillus subtilis CCFM1162, Bacteroides cellulosilyticus FTJSI-E-2, Bacteroides stercoris FNMHLBEIK-4, and Saccharomyces cerevisiae HN7-A5, were used to ferment Dendrobium officinale. The skin care activity of the resulting polysaccharides (F-DOP) was evaluated in cultured HaCaT and RAW 264.7 cells, and a mouse model. The results indicated that D. officinale medium promoted strain proliferation, and fermentation significantly enhanced polysaccharide yield (up to 1.42 g/L) compared to that without fermentation (0.76 g/L). Moreover, F-DOPs, especially after CCFM8631 fermentation, exhibited an excellent ability to attenuate sodium dodecyl sulfate-induced HaCaT cell injury (from 69.04 to 94.86%) and decrease nitric oxide secretion (from 42.86 to 22.56 μM) in lipopolysaccharide-stimulated RAW 264.7 cells. In vivo, CCFM8631-FDOP reduced the transdermal water loss rate, skin epidermal thickness, and interleukin 6, and enhanced the expression of filaggrin, improving 2,4-dinitrofluorobenzene-induced skin damage. Therefore, considering viable cell counts, polysaccharide yields, and skin care efficacy in vitro and in vivo, CCFM8631 is the most suitable strain to enhance the skin care activity of DOPs and possesses promising potential for applications in the cosmetics industry.