Heterozygous carriers of hemoglobin S and C (HbAS and HbAC) have a reduced risk of severe malaria but are not protected from Plasmodium falciparum infection, suggesting that the protection involves acquired immunity. During a blood meal, female Anopheles mosquitoes inject saliva that can elicit a host antibody response, which can serve as a proxy for exposure to Plasmodium infection. Previous studies have shown that the peptide gSG6-P1 of An. gambiae saliva is antigenic and highly Anopheles specific. Here, we used plasma samples from 201 Ghanaian children with wild-type hemoglobin (HbAA), HbAS, and HbAC to evaluate antibody levels against gSG6-P1 as a serological biomarker of Anopheles exposure and, therefore of P. falciparum infection risk. Malaria antigen (PfCSP, GLURP, Pfs230, and HB3VAR06)-specific IgG levels, demographic data, and data regarding P. falciparum infection and malaria control practices were also analyzed. Children with active P. falciparum infection had higher antibody levels against all antigens, and those with HbAS and HbAC had significantly higher antibody levels against Pfs230. Pfs230-specific IgG correlated negatively with gSG6-P1-specific IgG in children with HbAC. Our results highlight the importance of studying the role of hemoglobinopathies in malaria transmission to improve control interventions.