Background/Objectives: This study characterized an ethanol-eluted, semi-purified fraction (F4) from Myrtus communis L. leaves and compared its anti-inflammatory activity in free and nanoemulsified forms. Methods: F4 was obtained by C8 fractionation, examined by colorimetric assays, targeted LC–MS (SIM) and COX-2 docking, and incorporated into an oil-in-water nanoemulsion. Oral activity at 200 and 400 mg/kg was assessed in male Wistar rats with carrageenan-induced paw edema (seven groups; n = 6/group). The primary endpoint was the individual area under the curve (AUC) of edema over 1–5 h. Results: Targeted LC–MS tentatively annotated ten compounds. The total phenolic content of F4 was 186.75 ± 0.43 mg GAE/g, and apigenin had the most favorable predicted COX-2 docking score (−8.1 kcal/mol). The nanoemulsion measured 119.07 ± 16.28 nm on day 0 and showed no phase separation under stress tests. Free F4 and F4 nanoemulsion (F4 NE) reduced AUC versus the inflamed control, and F4 NE reduced AUC versus the blank nanoemulsion (Holm-adjusted p < 0.0001). Compared with free F4, nanoemulsification decreased mean AUC by 37.7% and 42.9% at 200 and 400 mg/kg (Holm-adjusted p = 0.0362 for both comparisons). After baseline adjustment, the difference persisted at 400 mg/kg (−2.94 mL·h; 95% CI −5.16 to −0.72; Holm-adjusted p = 0.0304) but not at 200 mg/kg (−1.61 mL·h; 95% CI −4.27 to 1.06; Holm-adjusted p = 0.2053). Conclusions: Orally administered F4 had anti-inflammatory activity, and nanoemulsification produced improved anti-inflammatory efficacy under the tested conditions, as shown by the lower cumulative edema. Bioavailability was not assessed; pharmacokinetic studies are needed to determine whether it underlies this effect.