Cancer is described as malignant cell proliferation. Normal cells lose control of their regulatory activities, which result in abnormal growth and division. Novel series of pyrazolo[1,5-a]pyrimidine analogues have been synthesized and assessed for anti-proliferative effect based on different studies focused on the significance of the pyrazolo[1,5-a]pyrimidine framework in tumor progression management. To assess the novel hits' antitumor efficacy, three tumor cell lines have been employed: MCF-7 for breast, HepG2 for liver, in addition to A549 for lung. According to cytotoxic screening, Compound 4d has been found to exhibit greater activity over doxorubicin, as shown by its IC50 = 0.72 ± 0.03 μM for MCF- 7 and IC50 = 0.14 ± 0.54 μM for HepG2 cell lines. Furthermore, it demonstrated a significant effect on the A549 cell line, exhibiting an IC50 = 2.33 ± 0.61 μM in comparison to doxorubicin (IC50 = 2.28, 3.67 and 2.62 μM respectively). Moreover, molecular docking of 4d has been achieved to highlight its binding interactions and affinity for the VEGFR-2 enzyme active site. Also, in silico results indicated that all compounds (4a-e) have high absorption while they can't cross the blood brain barrier.