Stereoselective synthesis of a small library of novel spiroheterocyclic hybrids including indolizine, oxindole, and substituted piperidine units has been accomplished in [bmim]Br using a [3 + 2] cycloaddition strategy in good yield and were tested for their anti-inflammatory activities. The effects of compounds (4a-o) against inflammation were studied using carrageenan-induced hind paw oedema, croton oil-induced ear oedema, and cotton pellet-induced granuloma models. Among the heterocyclic hybrids, compounds 4d, 4g, and 4o showed significant anti-inflammatory activities against acute and chronic inflammatory models. These compounds also showed significant inhibition of PGE2, TNF-α, and nitrite levels in carrageenan-induced hind paw oedema. Thus it is evident from our study that these novel spiroheterocyclic hybrids 4d, 4g, and 4o displayed significant anti-inflammatory effects that involve the reduction of PGE2, TNF-α, and nitrite levels.