A novel series of pyrimidine–pyrazole hybrids 4(a–h) was successfully synthesized via an efficient one-pot multicomponent strategy and comprehensively evaluated for their antibacterial potential. Among the synthesized derivatives, compounds 4b and 4d emerged as the most potent candidates, exhibiting remarkable inhibitory activity against Escherichia coli, Staphylococcus aureus, and Klebsiella pneumoniae. Furthermore, their excellent stability, reproducibility, and broad-spectrum antibacterial efficacy highlight their promising pharmacological potential. Collectively, these findings identify compounds 4b and 4d as valuable multifunctional lead scaffolds for further optimization and the development of next-generation bioactive therapeutics.