In this study, a series of novel 3-<i>seco</i>-A derivatives of the natural triterpenes α-amyrin (<b>1</b>) and 3-epilupeol (<b>2</b>) were synthesized by a one-pot radical scission-oxidation procedure and evaluated <i>in vitro</i> and <i>in vivo</i> for their capacity to inhibit the inflammatory process. For the <i>in vitro</i> studies, the <i>trans</i>-4-hydroxy-l-proline methyl ester derivatives (<b>1f</b> and <b>2f</b>) were consistently effective in inhibiting NO, IL-6, and TNF-α secretion, as well as inhibition of NF-κB activation, in RAW cells stimulated by LPS. The further <i>in vivo</i> anti-inflammatory study revealed that the <i>trans</i>-4-hydroxy-l-proline methyl ester derivatives (<b>1f</b> and <b>2f</b>), together with <b>1g</b>, were the most effective in inhibiting TPA-induced edema. Interestingly, the α-amyrin derivatives were the most potent inhibitors of COX-2, but inhibited COX-1 only to some extent. The hydroxyl derivative (<b>1c</b>) was selective for COX-2 inhibition (66.3 ± 1.1% at 17.5 μM) without affecting the COX-1 isoform and did not present toxicity. Molecular docking studies revealed that these compounds bind with their polar region in the cavity over Arg-120, and their lipophilic part is orientated to the HEM cofactor similarly to the natural substrate arachidonic acid in the catalytic site of COX-2. These results indicated that <i>seco</i>-A ursane derivatives could be considered promising candidates for the future development of selective NF-κB and COX-2 inhibitors.