In this study, poly (isobutylene-alt-maleic anhydride)(PMA)-coated spinel ferrite (MFe 2 O 4, where M= Fe, Co, Ni, or Zn) nanoparticles (NPs) were developed as carriers of the anticancer drugs doxorubicin (DOX) and methotrexate (MTX). Physical characterizations confirmed the formation of pure cubic structures (14–22 nm) with magnetic properties. Drug-loaded NPs exhibited tumor specificity with significantly higher (p< 0.005) drug release in an acidic environment (pH 5.5). The nanoparticles were highly colloidal (zeta potential=− 35 to− 26 mV) in deionized water, phosphate buffer saline (PBS), and sodium borate buffer (SBB). They showed elevated and dose-dependent cytotoxicity in vitro compared to free drug controls. The IC 50 values ranged from 0.81 to 3.97 μg/mL for HepG2 and HT144 cells, whereas IC 50 values for normal lymphocytes were 10 to 35 times higher (18.35–43.04 µg/mL). Cobalt ferrite (CFO) and zinc ferrite (ZFO) NPs were highly genotoxic (p< 0.05) in cancer cell lines. The nanoparticles caused cytotoxicity via oxidative stress, causing DNA damage and activation of p53-mediated cell cycle arrest (significantly elevated expression, p< 0.005, majorly G1 and G2/M arrest) and apoptosis. Cytotoxicity testing in 3D spheroids showed significant (p< 0.05) reduction in spheroid diameter and up to 74±8.9% of cell death after two weeks. In addition, they also inhibited multidrug resistance (MDR) pump activity in both cell lines suggesting effectivity in MDR cancers. Among the tested MFe 2 O 4 NPs, CFO nanocarriers were the most favorable for targeted cancer therapy due to excellent magnetic, colloidal, cytotoxic, and biocompatible aspects. However, detailed mechanistic, in vivo cytotoxicity, and magnetic-field-assisted studies are required to fully exploit these nanocarriers in therapeutic applications.