In this report, we propose the combination of computational methods and in vivo primary screening in zebrafish larvae and confirmatory in mice models as a novel strategy to accelerate anti-inflammatory drug discovery. Initially, a database of 1213 organic chemicals with great structural variability - 587 of them anti-inflammatory agents plus 626 compounds with other clinical uses - was divided into training and test groups. Atom-based quadratic indices - a TOMOCOMD-CARDD molecular descriptors family - and linear discriminant analysis (LDA) were used to develop a total of 13 models to describe the anti-inflammatory activity. The best model (Eq. (13)) shows an accuracy of 87.70% in the training set, and values of Matthews correlation coefficient (C) of 0.75. The robustness of the models was demonstrated using an external test set as validation method, i.e., Eq. (13) revealing classification of 88.44% (C = 0.77) in this series. All models were employed to develop ensemble a QSAR classification system, in which the individual QSAR outputs are the inputs of the aforementioned fusion approach. The fusion model was used for the identification of novel anti-inflammatory compounds using virtual screening of 145 molecules available in our in-house library of indazole, indole, cinnoline and quinoxaline derivatives. Out of these, 34 chemicals were selected, synthesized and tested in a lipopolysaccharide (LPS)-induced leukocyte migration assay in zebrafish larvae. This activity was evaluated based on leukocyte migration to the injury zone of tail-transected larvae. Compounds 18 (3 μM), 24 (10 μM), 25 (10 μM), 6 (10 μM), 15 (30 μM), 11 (30 μM) and 12 (30 μM) gave the best results displaying relative leukocyte migration (RLM) values of 0.24, 0.27, 0.35, 0.41, 0.17, 0. 26 and 0.27 respectively, date that suggest an anti-inflammatory activity of 76, 73, 65, 59, 83, 84 and 73%, respectively. Compound 18 was the most potent but showed high toxicity together with compound 6. Next, we used the tetradecanoylphorbol acetate (TPA)-induced mouse ear oedema model to evaluate the most potent compounds in the zebrafish larvae tail transection assay. All assayed compounds, with the exception of chemical 15, showed anti-inflammatory activity in mice. Compound 12 (VA5-13l, 2-benzyl-1-methyl-5-nitro-1,2-dihydro-3H-indazol-3-one) was the most active and completely abolished the oedema. Compounds 6, 11 and 24 showed inhibition percentages in the range of the reference drug (indomethacin), whereas compounds 18 and 25 reduced the oedema in a lesser extent (inhibition of 73 and 80%, respectively). In addition, all compounds except chemical 15, significantly reduced neutrophil infiltration, measured as myeloperoxidase activity on TPA application test. Compounds 6, 11, 12 and 18 showed values comparable to indomethacin (inhibition percentage of 61), but compounds 6 and 18 were toxic in zebrafish and showed unspecific cytotoxicity in murine macrophages at 100 μg/mL, while the remaining compounds 11, 12 and 25 were inactive at most levels. Evidently, this study suggests a new support structure (12, 11 and 24; a nitroindazolinone chemotype) that constitutes a novel promising lead and may represent an important therapeutic alternative for the treatment of inflammatory conditions.