Insecticides are widely used as the primary management strategy for controlling Myzus persicae, the devastating pest ravaging various vegetables, fruits, crops, and ornamentals. This study examined the susceptibility of M. persicae field populations to bifenthrin, fosthiazate, acetamiprid, spirotetramat, afidopyropen, and flonicamid while exploring the possible metabolic mechanisms of resistance. The study findings revealed that M. persicae field populations exhibited susceptible-to-moderate resistance to bifenthrin (resistance ratio (RR) = 0.94–19.65) and acetamiprid (RR = 1.73–12.91), low-to-moderate resistance to fosthiazate (RR = 3.67–17.00), and susceptible-to-low resistance to spirotetramat (RR = 0.70–6.68). However, all M. persicae field populations were susceptible to afidopyropen (RR = 0.44–2.25) and flonicamid (RR = 0.40–2.08). As determined by the biochemical assays, carboxylesterases were involved in the resistance cases to bifenthrin and fosthiazate, whereas cytochrome P450 monooxygenases were implicated in the resistance cases to acetamiprid. However, glutathione S-transferases were not implicated in the documented resistance of M. persicae field populations. Overall, the susceptibility of M. persicae field populations to flonicamid and afidopyropen—two unregistered insecticides in Saudi Arabia—suggests their potential as promising chemicals that can expand the various alternatives available for controlling this devastating pest. Although the detected moderate levels of resistance to bifenthrin, fosthiazate, and acetamiprid indicate a shift in the selection pressure of insecticides for M. persicae due to Saudi regulations, which have resulted in eventual obsolescence of conventional insecticides in favor of novel insecticides. Finally, rotational use of aforementioned insecticides can help in managing insecticide resistance in M. persicae.