As genetic interventions or extended caloric restriction cannot be applied in humans, many studies have been devoted to the identification of natural products that can prolong healthspan. 6-bromoindirubin-3'-oxime (6BIO), a hemi-synthetic derivative of indirubins found in edible mollusks and plants, is a potent inhibitor of Glycogen synthase kinase 3β (Gsk-3β). This pleiotropic kinase has been implicated in various age-related diseases including tumorigenesis, neurodegeneration and diabetes. Accordingly, 6BIO has shown anti-tumor and anti-neurodegenerative activities; nevertheless, the potential role of 6BIO in normal human cells senescence remains largely unknown. We report herein that treatment of human diploid skin fibroblasts with 6BIO reduced the oxidative load, conferred protection against oxidative stress-mediated DNA damage, and it also promoted the activation of antioxidant and proteostatic modules; these effects were largely phenocopied by genetic inhibition of Gsk-3. Furthermore, prolonged treatment of cells with 6BIO, although it decreased the rate of cell cycling, it significantly suppressed cellular senescence-related accumulation of biomolecular damage. Taken together, our presented findings suggest that 6BIO is a novel activator of antioxidant responses and of the proteostasis network in normal human cells; moreover, and given the low levels of biomolecules damage in 6BIO treated senescing cells, this compound likely exerts anti-tumor properties.