Skin health is associated with the day‐to‐day activity of fibroblasts. The primary function of fibroblasts is to synthesize structural proteins, such as collagen, extracellular matrix proteins, and other proteins that support the structural integrity of the skin and are associated with younger, firmer, and more elastic skin that is better able to resist and recover from injury. At sub‐nanomolar concentrations (0.03–0.3 nM), bryostatin‐1 and its synthetic analog, picolog (0.1–10 nM) sustained the survival and activation of human dermal fibroblasts cultured under the stressful condition of prolonged serum deprivation. Bryostatin‐1 treatment stabilized human skin equivalents (HSEs), a bioengineered combination of primary human skin cells (keratinocytes and dermal fibroblasts) on an extracellular matrix composed of mainly collagen. Fibroblasts activated by bryostatin‐1 protected the structural integrity of HSEs. Bryostatin‐1 and picolog prolonged activation of Erk in fibroblasts to promote cell survival. Chronic stress promotes the progression of apoptosis. Dermal fibroblasts constitutively express all components of Fas associated apoptosis, including caspase‐8, an initiator enzyme of apoptosis. Prolong bryostatin‐1 treatment reduced apoptosis by decreasing caspase‐8 and protected dermal fibroblasts. Our data suggest that bryostatin‐1 and picolog could be useful in anti‐aging skincare, and could have applications in tissue engineering and regenerative medicine. At sub‐nanomolar concentrations (0.03–0.3 nM), bryostatin‐1 and its synthetic analog, picolog (0.1–10 nM) sustained the survival and activation of human dermal fibroblasts cultured under the stressful condition of prolonged serum deprivation. Bryostatin‐1 treatment stabilized human skin equivalents (HSEs), a bioengineered combination of primary human skin cells (keratinocytes and dermal fibroblasts) on an extracellular matrix composed of mainly collagen. Fibroblasts activated by bryostatin‐1 protected the structural integrity of HSEs.