As malaria control and elimination efforts ramp up in Ethiopia, more sensitive tools for assessing exposure to coendemic Plasmodium falciparum and Plasmodium vivax are needed to accurately characterize malaria risk and epidemiology. Serological markers have been increasingly explored as cost-effective tools for measuring transmission intensity and evaluating intervention effectiveness. The objectives of this study were to evaluate the efficacy of a panel of 10 serological markers as a proxy for malaria exposure and to determine underlying risk factors of seropositivity. We conducted cross-sectional surveys in two sites of contrasting malaria transmission intensities in southwestern Ethiopia: Arjo in Oromia Region (low transmission) and Gambella in Gambella Regional State (moderate transmission). We measured antibody reactivity against six P. falciparum (AMA-1, CSP, EBA175RIII-V, MSP-142, MSP-3, RH2ab) and four P. vivax (DBPII[Sal1], EBP2, MSP-119, RBP2b) targets. We used mixed effects logistic regressions to assess predictors of seropositivity. Plasmodium spp. infection prevalence by quantitative polymerase chain reaction was 1.36% in Arjo and 10.20% in Gambella. Seroprevalence and antibody levels against all 10 antigens were higher in Gambella than in Arjo. We observed spatial heterogeneities in seroprevalence across Arjo and smaller variations across Gambella. Seroprevalence in both sites was lowest against PfCSP and highest against PfAMA-1, PfMSP-142, and PvMSPS-119. Male sex, age, and agricultural occupation were positively associated with seropositivity in Arjo; associations were less pronounced in Gambella. Our findings demonstrate that seroprevalence and antibody levels to specific Plasmodium antigens can be used to identify high-risk groups and geographical areas where interventions to reduce malaria transmission should be implemented.