Chalcones are interesting compounds because of their pharmacological versatility, in this work a series of three nitro-substituted chalcones (compounds 3a–c), modified at the B aromatic ring, was synthesized via a classical Claisen–Schmidt condensation under mild hydroalcoholic conditions at room temperature. This method proved efficient and reproducible, affording excellent yields above 90% for all three derivatives. Structural elucidation was achieved through spectroscopic techniques including IR, ¹H and ¹³C NMR, all of which confirmed the expected α,β-unsaturated ketone frameworks with nitro substitutions. To evaluate the anti-inflammatory potential of the synthesized compounds, an in vivo carrageenan-induced hind paw edema model in rats was employed. This model is widely used for assessing acute inflammatory responses. Compounds 3a–c were administered prior to carrageenan injection, and paw volume was measured over time. All compounds demonstrated a significant protective effect against inflammation, with compound 3b showing the highest activity within the series. The anti-inflammatory data were analyzed statistically using ANOVA followed by Tukey’s post hoc test. Additionally, a comparative analysis was conducted between these B-ring-substituted nitrochalcones and previously reported chalcones bearing substitutions on ring A. The findings suggest that the position and nature of substitution play a crucial role in modulating anti-inflammatory activity, highlighting the potential of nitrochalcones as candidates for further pharmacological development.