Background/Objectives: Curcuma longa is widely recognized for its antioxidant, antimicrobial, and wound-related biological effects. The present study aimed to compare two extracts prepared from organic turmeric powder (Curcuma longa), using distilled water (CUR-H2O) and 96% ethanol (CUR-EtOH), in terms of extraction yield, phytochemical profile, antimicrobial activity, and in vitro biological behavior relevant to future oral-health-oriented applications. Methods: The extracts were prepared by maceration followed by ultrasound-assisted processing, concentration, and lyophilization. Their antioxidant potential (AOP) was evaluated by DPPH assay, total phenolic content (TPC) by the Folin–Ciocalteu method, and targeted polyphenolic profile by UHPLC-MS. Antimicrobial activity was assessed by broth microdilution against Streptococcus mutans, Streptococcus oralis, and Candida albicans. In vitro biological activity was investigated on HaCaT keratinocytes. Results: CUR-EtOH extract showed a higher extraction yield than CUR-H2O (5.13% vs. 2.01%), higher AOP (69.54 ± 0.49% vs. 53.35 ± 0.30%), and a higher TPC (163.87 ± 0.32 vs. 78.05 ± 0.28 mg GAE/g dry extract). Consistent with these TPC results, UHPLC-MS revealed a richer targeted polyphenolic profile in CUR-EtOH extract, particularly in terms of p-coumaric and ferulic acid derivatives. CUR-EtOH extract was more active against the tested oral streptococci, especially S. mutans (MIC 10 µL vs. 60 µL for CUR-H2O), whereas CUR-H2O extract showed a slightly better antifungal effect against C. albicans (MIC 60 µL vs. 80 µL). In HaCaT cells, CUR-H2O extract exhibited the more favorable compatibility profile, while CUR-EtOH extract showed stronger cytotoxicity, despite promoting faster wound-gap closure at 10 µg/mL. Conclusions: The extraction solvent strongly influenced both the chemical profile and biological behavior of the turmeric-powder-derived extracts. These findings suggest that solvent selection may be used to tailor the balance between antimicrobial efficacy and epithelial compatibility in future turmeric-powder-derived preparations intended for oral-health-oriented applications.
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