AbstractAccording to the encouraging biological activity and low cytotoxicity profile of thiazolyl‐pyrazole hybrid, many researchers are making efforts in this research area. 2‐(2‐(5‐Acetyl‐4‐methylthiazol‐2‐yl)hydrazono)acenaphthylen‐1(2H)‐one (3) was synthesized by the reaction of acenaphthenequinone‐thiosemicarbazone (1) with 3‐chloroacetylacetone (2) and utilized as a precursor for the production of various thiazolyl‐pyrazole compounds. The reaction of 3 with DMF‐DMA followed by treating the produced enaminone 4 with hydrazines furnished the corresponding thiazolyl‐pyrazoles 5 a–c. In addition, 1,3‐dipolar cycloaddition of enaminone 4 with α‐ketohydrazonyl chlorides 6 through a regioselective manner gave thiazolyl‐pyrazoles 7 a–c. The reaction of 3 with arylhydrazines yielded the corresponding hydrazones 8 a–c, which were subjected to Vilsmeier formylation reaction and furnished the thiazolyl‐pyrazoles 9 a–c. Meanwhile, the synthesized thiazolyl‐pyrazoles were screened to discover their antibacterial, antifungal, antioxidant, and antitumor activities. The antibacterial screening revealed that derivatives 7 a–c, 8 a–c, and 9 a–c demonstrated minimal inhibition concentrations toward B. subtilis and S. typhimurium. While derivatives 7 c and 9 c showed respectable antifungal effectiveness against C. albicans. Further, antioxidant effectiveness of the synthesized derivatives 7 a–c and 9 a–c revealed antioxidant activity superior to derivative 8 a–c and 5 a–c compared to ascorbic acid. Likewise, thiazolyl‐pyrazole derivatives 5 a–c displayed higher cytotoxic efficacy than their corresponding derivatives 9 a–c, 8 a–c and 7 a–c, respectively.