The degradation of extracellular matrix proteins such as collagen and elastin with aging leads to skin sagging. Polycaprolactone (PCL) microspheres are used as facial fillers because of their ability to provide volume, biodegradability, and collagen-stimulating properties. The direct biological effects of PCL microspheres on fibroblasts, particularly in stimulating sustained collagen production, require further investigation. We detected the safety and effect of PCL microspheres on human fibroblasts and investigated new collagen synthesis and the thickness of C57BL/6 mouse skin. Through an RNA-seq analysis of differentially expressed genes, we identified a key regulator of collagen production in PCL-stimulated fibroblasts. Our research revealed that PCL microspheres are safe for human fibroblasts, promoting their proliferation and increasing new collagen synthesis and skin thickness. We identified sterile alpha motif domain containing 11 (SAMD11) as a key regulator of collagen production in PCLstimulated fibroblasts through an RNA-seq analysis. By increasing SAMD11 expression, PCL microspheres increase collagen synthesis and rejuvenate skin through the upregulation of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1). This study elucidates the mechanism by which SAMD11 regulates the effects of PCL microspheres as collagen stimulants for skin rejuvenation, providing a foundation for the future development and refinement of similar materials.