Evaluating a novel fungal strain’s pathogenicity to important pests and their involved immune responses may give crucial data on a broad scale for future use in pest management strategies. Date palms are mostly destroyed by invading populations of red palm weevils; thus, developing natural biopesticides for them requires a comprehensive screening program of plant secondary metabolites. In this research, we examined the pathogenicity of a new strain of Beauveria bassiana on an important agricultural pest, Rhynchophorus ferrugineus, by measuring the relative activity of defensive enzymes and detoxifying enzymes in certain larval instars. Our findings reveal that the B. bassiana strain may infect the instars of R. ferrugineus, and its pathogenicity to the larvae steadily increases as the spore concentration increases. Seven days after inoculation, the LC50 (the median lethal concentration) of B. bassiana was 490.42 × 105 and 2974.47 × 108 spores/mL for the second and fourth instar R. ferrugineus, respectively, and the LC50 of B. bassiana for each R. ferrugineus instar decreased with infection time, indicating a significant dose effect. Infected R. ferrugineus larvae of the second instars showed considerable changes in the activity of both protecting and detoxifying enzymes (peroxidase, catalase, superoxide dismutase, Cytochrome P450, glutathione S transferase (GST), and esterase) as infection time progressed. In addition, R. ferrugineus larvae that were infected with B. bassiana had enzyme activity that persisted from 24 to 48 h, which was much longer than in the control group. Lethality of B. bassiana resulted in elevated expressions of GST, Esterase, and Cytochrome P450 responsive genes. In conclusion, the results of this research indicate that B. bassiana may be utilized as a bio-insecticide to suppress young larvae of R. ferrugineus in an integrated pest management program.