The rising threat of insecticide resistance in malaria vectors restricts the effectiveness of global malaria control initiatives. The Anopheles gambiae complex is a group of efficient vectors that has demonstrated extensive resistance to copious insecticides, particularly pyrethroids (permethrin). Consequently, alternative insecticides with different mechanisms of action, such as chlorfenapyr, are being applied frequently. Target site mutations, such as knockdown resistance (kdr) mutations (L1014F/S) in the voltage-gated sodium channel gene, along with increased metabolic detoxification mediated by cytochrome P450 monooxygenases, glutathione S-transferases, and esterases, are associated with permethrin resistance in An. gambiae complex. Conversely, chlorfenapyr, a novel insecticide involving metabolic activation, has been introduced as an alternative. Understanding these differential and overlapping resistance mechanisms is vital for strategic deployment of insecticides and designing effective resistance management programs. This review evaluates the susceptibility patterns of An. gambiae complex to both permethrin and chlorfenapyr, an alternative insecticide with a novel mode of action, while emphasizing their molecular resistance mechanisms and implications for malaria vector control. More focus is given to the Interceptor® G2 (IG2) long-lasting insecticidal net, which combines alpha-cypermethrin and chlorfenapyr to enhance the control of resistant mosquito populations. Compared to previous reviews, this paper provides an integrated analysis of the synergetic mechanism of IG2 that circumvents resistance, delay its spread, and revamps the efficacy of malaria interventions. By highlighting recent findings from field trials and molecular studies, this review underscores the need for strategic deployment, resistance surveillance, and policy support to sustain the effectiveness of dual-insecticide tools in endemic regions.