The balance of collagen and elastic fibers is crucial for skin structure, appearance, and function. As interest in skin regeneration and anti-aging grows, identifying compounds that stimulate elastogenesis remains a significant challenge. Many current treatments offer limited effectiveness, underscoring the need for advanced approaches in wound healing and regenerative medicine. Modulating extracellular matrix (ECM) production in dermal fibroblasts is a promising strategy for developing pharmacological therapies aimed at skin regeneration, wound healing, and anti-aging. In this study, a panel of pharmacologically active compounds was evaluated for their effects on primary human dermal fibroblasts. The tested compounds – retinoic acid (RA), dexamethasone (DXM), minoxidil sulfate (MNX), transforming growth factor beta 1 (TGF-β1), insulin-like growth factor 1 (IGF-1), copper sulfate (CuSO₄), dill extract (DE), magnesium ascorbyl phosphate (MAP, a stable vitamin C derivative), heparin (HEP), and γ-aminobutyric acid (GABA) – represent diverse biochemical classes and mechanisms of action. Pharmacological profiling enabled a comparative evaluation and ranking of compounds based on their ECM-modulating efficacy, viz. DXM, DE, IGF-1, HEP, RA, and TGF-β1 emerging as the most promising candidates. Moreover, scarring potential, safety, and cytotoxicity were evaluated in vitro . Notably, HEP, IGF-1, RA, and DXM also induced transient morphological changes in fibroblasts, which resolved at later time points. While these effects may reflect adaptive responses, potential long-term consequences cannot be excluded and need further investigation. These findings support further preclinical development of selected compounds as candidates for dermal therapeutics and skin regeneration strategies.