Recently, cancer research protocols have introduced clinical-stage spirooxindole-based MDM2 inhibitors. However, several studies reported tumor resistance to the treatment. This directed efforts to invest in designing various combinatorial libraries of spirooxindoles. Herein, we introduce new series of spirooxindoles via hybridization of the chemically stable core spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one and the pyrazole motif inspired by lead pyrazole-based p53 activators, the MDM2 inhibitor BI-0252 and promising molecules previously reported by our group. Single crystal X-ray diffraction analysis confirmed the chemical identity of a representative derivative. Fifteen derivatives were screened for cytotoxic activities via MTT assay against a panel of four cancer cell lines expressing wild-type p53 (A2780, A549, HepG2) and mutant p53 (MDA-MB-453). The hits were8hagainst A2780 (IC50= 10.3 µM) and HepG2 (IC50= 18.6 µM),8magainst A549 (IC50= 17.7 µM), and8kagainst MDA-MB-453 (IC50= 21.4 µM). Further MTT experiments showed that8hand8jpotentiated doxorubicin activity and reduced its IC50by at least 25% in combinations. Western blot analysis demonstrated that8kand8mdownmodulated MDM2 in A549 cells. Their possible binding mode with MDM2 were simulated by docking analysis.