Current acne therapies face major limitations, including antibiotic resistance and skin irritancy. In this study, a synergistic strategy combining cryptotanshinone and madecassoside was developed through functional complementarity. Antibacterial activity against Cutibacterium acnes was evaluated using minimum inhibitory concentration (MIC) and inhibition zone assays, while cytotoxicity was assessed using human keratinocytes (HaCaTs). Anti-inflammatory efficacy was quantified by measuring tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and prostaglandin E₂ (PGE₂) in lipopolysaccharide-stimulated macrophages and a copper sulfate (CuSO₄)-induced zebrafish inflammatory model. Systemic safety was examined in zebrafish models (developmental toxicity and sodium dodecyl sulfate-induced irritation). Finally, macroscopic severity, histopathology, and serum cytokines were used to assess an oleic acid-induced rat acne model. Cryptotanshinone inhibited Cutibacterium acnes (minimum inhibitory concentration = 62.5 μg/mL) but exhibited cytotoxicity (>5 μg/mL) and irritancy (≥1000 μg/mL). Madecassoside eliminated cryptotanshinone-induced cytotoxicity and reduced irritation. Importantly, the combination maintained antibacterial efficacy while synergistically enhancing anti-inflammatory effects, achieving a 94% reduction in follicular hyperkeratosis compared with 39% for cryptotanshinone alone (p < 0.01), alongside normalization of histopathology and cytokine levels. In conclusion, madecassoside functionally complements cryptotanshinone by neutralizing its cytotoxicity and irritancy, enabling a safe, synergistic therapy that concurrently targets antibacterial and anti-inflammatory pathways in acne pathogenesis