Nowadays, the use of pesticides is, as before, the most common way to control arthropod plant pests and the ectoparasites of animals. The sublethal effects of pesticides on insects can appear at different levels, from genetics to populations, and the study of these effects is important for a better understanding of the environmental and evolutionary patterns of pesticidal resistance. The current study aimed to assess the sublethal effects of chlorfenapyr and fipronil on the activities of detoxifying enzymes (carboxylesterase—CarE, acetylcholinesterase—AChE, glutathione-S-transferase—GST, and cytochrome P450 monooxygenase—P450) in adults Musca domestica L. The insects were exposure to insecticides by a no-choice feeding test and the enzyme activities and the AChE kinetic parameters were examined in female and male specimens at 24 h after their exposure. According to Tukey’s test, the CarE activity was statistically significantly decreased by 29.63% in the females of M. domestica after an exposure to chlorfenapyr at a concentration of 0.015% when compared to the controls (p ≤ 0.05). An exposure to the sublethal concentration of fipronil (0.001%) was followed by a slightly decrease in the specific activity (33.20%, p ≤ 0.05) and the main kinetic parameters (Vmax, Km) of AChE in females in comparison with the control values. The GST and P450 activities had not significantly changed in M. domestica males and females 24 h after their exposure to chlorfenapyr and fipronil at sublethal concentrations. The results suggest that the males and females of M. domestica displayed biochemically different responses to fipronil, that is a neurotoxin, and chlorfenapyr, that is a decoupler of oxidative phosphorylation. Further research needs to be addressed to the molecular mechanisms underlying the peculiarities of the insect enzyme responses to different insecticides.