Two new series of pyrazole derivatives 10a-f and 11a-f with selective COX-2 inhibition pharmacophore and oxime/nitrate moieties as NO donor moiety were designed, synthesized and tested for anti-inflammatory, cytotoxic activities and NO release. Compounds 10c, 11a, 11e were more selective for COX-2 isozyme (S.I. = 25.95, 22.52 and 21.54 respectively) in comparison to celecoxib (S.I. = 21.41). Regarding anti-cancer activity, all synthesized compounds were screened by the National Cancer Institute (NCI), Bethesda, USA for anticancer activity against 60 human cancer cell lines representing the following cancer types: leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancers. Compounds 10c, 11a, 11e were found to be the most potent inhibitors on breast, ovarian and melanoma cell lines (MCF-7, IGROV1 and SK-MEL-5), compound 11a causing 79 % inhibition in case of MCF-7, 78.80 % inhibition in case of SK-MEL-5 and unexpected cell growth −26.22 % inhibition in case of IGROV1 (IC50 = 3.12, 4.28, 4.13 μM respectively). On the other hand, compounds 10c and 11e showed lower inhibition on the same cell lines with IC50 = 3.58, 4.58, 4.28 μM respectively for 10c, IC50 = 3.43, 4.73, 4.43 μM respectively for 11e. Furthermore, DNA-flow cytometric analysis showed that compound 11a induces cell cycle arrest at G2/M phase leading to cell proliferation inhibition and apoptosis. Additionally, these derivatives examined against F180 fibroblasts to investigate their selectivity indexes. The pyrazole derivative with internal oxime 11a was the most potent compound against most used cell lines especially MCF-7, IGROV1 and SK-MEL-5 (IC50 = 3.12, 4.28, 4.13 μM respectively) with 4.82-fold selectivity towards MCF-7 than F180 fibroblasts. Moreover, oxime derivative 11a showed potent aromatase inhibitory activity (IC50 16.50 μM) when compared with reference compound letrozole (IC50 15.60 μM). All compounds 10a-f and 11a-f released NO in a slow rate (0.73–3.88 %) and the six derivatives 10c, 10e, 11a, 11b, 11c and 11e were the highest NO releasers (3.88, 2.15, 3.27, 2.27, 2.55 and 3.74 % respectively). Herein structure based and ligand based studies were implemented to under stand and evaluate the compounds activity for further in vivo and preclinical studies. Docking mode of final designed compounds with celecoxib (ID: 3LN1) represented that their triazole ring adopted as the core aryl in Y shaped structure. Regarding aromatase enzyme inhibition, docking was carried out with ID: 1 M17. The internal oxime series was more active as anticancer because of their ability to form extra HBs with receptor cleft.