New pyrazoline derivatives 7a–f, 11a–f, and 15a–f were synthesized via 1,3-cycloaddition of nitrileimines with α,β-unsaturated ketones using ecofriendly catalysts e.g., iodine or THAC in water. A comparative study between the utility of triethylamine and Na2CO3/THAC as catalyst was achieved. Anticancer activity against colon cancer HT29 was screened for sixteen pyrazoline derivatives. 7a and 11f derivatives were more potent than doxorubicin, while 11d analog was almost equipotent to it. (QSAR) was performed to select out the predominant descriptors affecting the anticancer activity. Lipophilic, topological steric, and electronic dipole descriptors play a decisive role in determining the activity. Three models were generated based on Multiple Linear and Partial Least Square analysis with Leave One Out validation technique.