In the present investigation, a series of novel pyrazole–pyrimidine derivatives (3a–i) were rationally designed and synthesized via Claisen–Schmidt condensation, followed by evaluation of their antimicrobial potential against a panel of bacterial and fungal strains. Among the synthesized compounds, derivative 3c demonstrated remarkable inhibitory activity with a minimum inhibitory concentration (MIC) of 62.5 µg/mL against Pseudomonas aeruginosa (MTCC-1688) and Aspergillus niger (MTCC-281), whereas derivative 3i exhibited broad-spectrum equipotent activity against all the tested bacterial and fungal strains, highlighting its potential as a promising lead candidate for further development.