Dangerous Paracoccus marginatus papaya mealybugs cause considerable threats and challenges to cassava production and processing. The deployment of resistant cultivars offers effective, economical and eco-friendly management strategies for pest management. We utilized P. marginatus mortality, development and reproduction to evaluate the resistance of fteen cassava cultivars and conducted physiological and biochemical analyses when P. marginatus was fed on two resistant cultivars (Myanmar, C1115) and three susceptible cultivars (BRA900, Bread, SC205). Signi cantly lower digestive (amylase, sucrase, lipase), detoxi cation (glutathione-S-transferase and carboxylesterase) and antioxidant, including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and polyphenol oxidase (PPO), enzyme activities were observed in P. marginatus feeding on resistant cultivars compared to susceptible cultivars. For resistant cultivars, a signi cant reduction was found in nutritional components containing free amino acids, nitrogen, soluble sugars and the secondary metabolite malondialdehyde. Additionally, signi cantly higher enzymatic activity (SOD, CAT, POD and PPO) levels and secondary metabolite quantities (total phenol and tannins) were found in resistant cultivars induced by P. marginatus compared with susceptible ones. Additionally, RT-qPCR tests showed that the transcripts of ten genes involved in nutrition, secondary metabolites and antioxidant activities were consistent with their physiology and biochemistry changes. Thus, resistant cultivars prevented P. marginatus populations from suffering lower P. marginatus damage by elevating secondary metabolite contents and antioxidant activities, reducing nutrition levels and decreasing enzymatic activities. This study will be bene cial in determining the important indexes for developing standard regulations to evaluate P. marginatus-resistant cassavas, helping the development of effective strategies for pest management. Key MessageWe identi ed and characterized the resistance of fteen cassava cultivars to P. marginatus.The activities of digestive, detoxi cation and antioxidant enzymes of P. marginatus were signi cantly inhibited after they were fed on resistant cultivars.Lower contents of nutritional components and malondialdehyde, and higher levels of toxic secondary metabolites together with antioxidant enzyme activities were observed in resistant cassava cultivars infested with P. marginatus.The resistant cultivars prevented P. marginatus populations from suffering lower P. marginatus damage by elevating secondary metabolite contents and antioxidant activities, reducing nutrition levels and decreasing enzymatic activities.