An efficient synthesis of substituted 4-acetyl-5,6-diphenylpyridazin-3(2H)-one derivatives has been achieved using green chemistry tools such as grinding and microwave heating compared to conventional heating. In this work, 4-acetyl-5,6-diphenylpyridazin-3(2H)-one derivative attached to Schiff-bases, chalcones, pyridine, and pyrrole moieties have been prepared with the aim to possess engaging biological and pharmacological activities. The Schiff-base 2 was obtained by reacting 4-acetyl-5, 6-diphenylpyridazin-3(2H)-one 1 with p-amino acetophenone, and the corresponding chalcones 3a-d were obtained by reacting the Schiff-base 2 with the relevant aldehydes. Novel pyridinyl-pyridazinones 5a-h and pyrrole-pyridazinone derivatives 6a-h were synthesized by the reaction of chalcones 3a-d with different acetyls and aldehydes under grinding, microwave irradiations or under reflux conditions. The synthesized compounds were tested for both Gram-positive and Gram-negative antibacterial activity, antifungal, and anticancer activities. These substances were also evaluated using analytical and spectral data, such as 1HNMR and mass spectrum analysis.