Evaluating the safety of botanical extracts for cosmetics has become mandatory, but it is often challenging because of their phytochemical complexity and limited toxicological data. In this study, the safety of aqueous Sophora flavescens root extract (SFRE), widely used in cosmetics, was assessed using an integrated approach combining in vitro, in silico, margin of safety (MoS), threshold of toxicological concern (TTC), and history of safe use (HSU). Chemical characterization was performed by literature review and LC–MS/MS analysis. SFRE was classified as non-irritant in in vitro skin and eye irritation tests conducted according to OECD TG439 and 492. Whole-extract and constituent-level in silico analysis and literature evaluation were conducted to assess genotoxicity and skin sensitization potential. For systemic toxicity, a 13-week oral repeat dose no-observed-adverse-effect level (NOAEL) of 10 mg/kg bw/day for a decocted Sophorae radix extract was employed without compositional adjustment to calculate the acceptable systemic exposure dose of 0.10 mg/kg bw/day, which was slightly lower than the current usage of SFRE in cosmetics (up to 0.13 mg/kg/day). The TTC approach revealed that many bioactive constituents fell outside the applicability domain due to steroid moieties. HSU data from dietary supplements (32–64.67 mg/kg/day) could support the safety of the current use of SFRE in cosmetics. The findings highlight that a combined, case-by-case application of MoS, TTC, and HSU is essential for the robust safety assessment of complex botanical ingredients.