Background Long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) are the main malaria vector control measures deployed in Kenya. Widespread pyrethroid resistance among the primary vectors in Western Kenya has necessitated the re-introduction of IRS using an organophosphate insecticide, pirimiphos-methyl (Actellic® 300CS), as a pyrethroid resistance management strategy. Evaluation of the effectiveness of the combined use of non-pyrethroid IRS and LLINs has yielded varied results. We aimed to evaluate the effect of non-pyrethroid IRS and LLINs on malaria indicators in a high malaria transmission area. Methods We reviewed records and tallied monthly aggregate of outpatient department (OPD) attendance, suspected malaria cases, those tested for malaria and those testing positive for malaria at two health facilities, one from Nyatike, an intervention sub-county, and one from Suba, a comparison sub-county, both located in Western Kenya, from February 1, 2016, through March 31, 2018. The first round of IRS was conducted in February–March 2017 in Nyatike sub-county and the second round one year later in both Nyatike and Suba sub-counties. The mass distribution of LLINs has been conducted in both locations. We performed descriptive analysis and estimated the effect of the interventions and temporal changes of malaria indicators using Poisson regression for a period before and after the first round of IRS. Results A higher reduction in the intervention area in total OPD, the proportion of OPD visits due to suspected malaria, testing positivity rate and annual malaria incidences were observed except for the total OPD visits among the under 5 children (59% decrease observed in the comparison area vs 33% decrease in the intervention area, net change -27%, P <0.001). The percentage decline in annual malaria incidence observed in the intervention area was more than twice the observed percentage decline in the comparison area across all the age groups. A marked decline in the monthly testing positivity rate (TPR) was noticed in the intervention area, while no major changes were observed in the comparison area. The monthly TPR reduced from 46% in February 2016 to 11% in February 2018, representing a 76% absolute decrease in TPR among all ages (RR = 0.24, 95% CI 0.12–0.46). In the comparison area, TPR was 16% in both February 2016 and February 2018 (RR = 1.0, 95% CI 0.52–2.09). A month-by-month comparison revealed lower TPR in Year 2 compared to Year 1 in the intervention area for most of the one year after the introduction of the IRS. Conclusions Our findings demonstrated a reduced malaria burden among populations protected by both non-pyrethroid IRS and LLINs implying a possible additional benefit afforded by the combined intervention in the malaria-endemic zone.