•Three different dendritic scaffolds of naproxen conjugates are synthesized.•The different bond-type dendritic drugs are compared with release properties in vitro.•Self-immolative dendritic prodrugs release naproxen after a single enzymatic activation step.•Dendritic prodrugs exhibit significant anti-inflammatory activity in vivo.•Dendritic prodrugs cause less gastric ulceration and disruption.It has been reported that delivery systems based on dendritic prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) improved the properties of drug molecules and reduced the side effects and irritation on the gastric mucosa. To find a more effective way in NSAIDs dendritic prodrugs, in this paper, three different dendritic scaffolds of enzymatically cleavable naproxen conjugates have been synthesized in a convergent approach and well characterized by NMR and MS techniques. These self-immolative dendritic NISADs prodrugs programmed to release multiple molecules of the potent naproxen after a single enzymatic activation step, and in 50% human plasma, the drug released from the compound T3 reaching 47.3% after 24 h in vitro assay. Moreover, all prodrugs were also found to maintain more significant anti-inflammatory activity, no significant cytotoxicity against HEK293 cells and less degree of ulcerogenic potential in vivo than their monomeric counterpart naproxen. These results provided an effective entry to the development of new dendritic NSAIDs prodrugs.In this paper, three different dendritic scaffords of enzymatically cleavable naproxen conjugates have been synthesized in a convergent approach and well characterized by NMR and MS techniques. The efficient release of the active drug moiety occurred by the cleavage of different benzyl ester or amide triggers by enzymatic activation of hydrophobic self-immolative dendritic prodrugs, cleavage properties and cytotoxicity of the new conjugates are also presented. Moreover, all prodrugs were also found to possess more significant anti-inflammatory activity and less degree of ulcerogenic potential in vivo than their monomeric counterpart naproxen.