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Malaria remains a significant public health challenge in Angola, particularly in the Cuando Cubango province. This study aimed to characterise the local Anopheles mosquito population and evaluate the impact of indoor residual spraying (IRS) on key entomological indicators. Mosquito collections were conducted indoors at three sites over five months using CDC light traps and Prokopack aspirators. Ten Anopheles species were identified, with An. funestus s.s. being the predominant vector, accounting for 91.7% of the Funestus group. The overall Plasmodium falciparum circumsporozoite protein (CSP) infection rate was 9.2%, with Makua exhibiting the highest rate (10.2%). Following IRS, the indoor resting density of the Funestus group decreased significantly in Makua and Agostinho Neto. In Makua, An. funestus s.s. CSP infection rates decreased by 55% following IRS implementation, however, this reduction was not statistically significant. Knockdown resistance mutations were detected in An. arabiensis and An. gambiae s.s. The 2020/2021 IRS campaign achieved 92.2% coverage, reaching 334,604 individuals. These findings highlight the importance of sustained vector control efforts and entomological surveillance in any vector control initiative and provide valuable insights for malaria control strategies in Cuando Cubango.