<p><i>Culex quinquefasciatus</i> Say (Diptera: Culicidae) is an important vector that spreads a number of diseases like lymphatic filariasis, Rift Valley fever, West Nile fever, Zika virus, and Saint Louis encephalitis. Due to long-term exposure to insecticides applied during vector control programs, these mosquito populations exhibit varying degrees of resistance in response to distinct selection pressures. Therefore, it is imperative to assess their resistance status before deploying any control programs. The present study examined the resistance status of wild <i>Cx. quinquefasciatus</i> mosquito larvae against two commonly used insecticides (cyphenothrin and temephos) from sub-Himalayan West Bengal. This study also examined the activity of carboxylesterases and the levels of cytochrome P450 enzymes in wild larvae of <i>Cx. quinquefasciatus</i> mosquitoes from three districts in the northern part of West Bengal. The expression pattern of selected P450 and esterase genes (<i>Est A</i>, <i>Est B</i>, <i>CYP6AA7</i>, <i>CYP9J40</i>, <i>CYP9J45</i>) has been assessed to investigate their involvement in metabolic resistance in this mosquito species. Most of the populations were fully resistant to cyphenothrin, whereas few were resistant to temephos. Significantly high activities and levels of targeted detoxifying enzymes were observed among all the wild populations. Overexpression of the <i>Est B</i>, <i>CYP6AA7</i>, and <i>CYP9J40</i> genes was observed in most wild populations compared to susceptible ones. From this study, it can be suggested that metabolic resistance has an important role in developing resistance among <i>Cx. quinquefasciatus</i> populations of this region. Proper mapping of insecticide resistance should be done before using any insecticides.</p>