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Abstract Background Despite its effectiveness, the optimal use of the combination of insecticide-treated nets (ITN) and intermittent preventive treatment during pregnancy with sulfadoxine–pyrimethamine (IPTp-SP) remains low in malaria-endemic areas. Therefore, this study analyzed its variations and predictors in Guinea. Methods This study was a secondary analysis of the 2012 and 2018 Guinea Demographic and Health Surveys (DHS). It included women who had given birth 3 years before each DHS, slept on ITN and took at least one dose of SP. Use was complete if a pregnant woman slept on ITNs and took SP (at least two doses in 2012; at least three doses in 2018). Moran indices were used to determine spatial autocorrelation and classification methods to identify malaria preventive measures (MPM) predictors. Results In 2012, 60.88% of pregnant women had incomplete use of MPMs compared with 79.11% in 2018. Associated factors with incomplete MPMs in 2012 were as follows: having an indirect link with the head of household (AOR = 2.23, 95% CI 1.08–4.61) and performing at least 4 ANC visits (AOR = 0.66, 95% CI 0.44–0.99). In 2018: Living in households of 2 to 5 people (AOR = 0.54, 95% CI 0.36–0.80), have a man as the head of the household (AOR = 0.56, 95% CI 0.35–0.89), perform the first ANC in the second trimester of pregnancy (AOR = 0.74, 95% CI 0.54–0.99), perform at least 4 ANC visits (AOR = 0.47, 95% CI 0.36–0.62), have a job (AOR = 0. 67, 95% CI 0.50–0.88), give birth in a public health facility (AOR = 0.53, 95% CI 0.39–0.72) and the middle wealth quintile (AOR = 1.56, 95% CI 1.07–2.26). Analyses revealed a global autocorrelation (Moran index = 0.0009, p = 0.2349) and high–high clusters in Mamou in 2012. In 2018, autocorrelation was found (I Moran = 0.0169, p ≤ 0.05), with spatial clusters in 4 regions. Conclusion The link with the head of household and the number of ANC visits were the main factors in MPMs. It is essential to implement strategies at the household level and health system level and monitor them to reduce inequality across regions.