Introduction: The onset of Plasmodium falciparum (P. falciparum) resistance to antimalarial drugs requires the careful surveillance of African parasite populations. Genomic tools are implemented to detect evolutionary changes that could impact malaria control and elimination strategies. Here, we evaluate the genome-wide pattern of selection and sequence variation in P. falciparum populations in Abidjan, Côte d’Ivoire. Methods: The study was conducted in three localities of Abidjan from 2013 to 2014. We collected 70 blood samples after receiving written informed consent from patients above two years of age. After extracting P. falciparum and human DNA from isolates, we performed whole-genome sequencing and used population genomics approaches to investigate the genetic diversity and complexity of infections and identify loci under positive directional selection. Results: We observed an excess of rare variants in the population, showing a clear mutation process in the isolates. Moderate Fst estimates (0.3) was detected for surfin, an immune invasion gene family. Seven iHS regions that had at least two SNPs with a score > 3.2 were identified. These regions code for genes that have been under strong directional selection. Two of these genes were the chloroquine resistance transporter (crt) on chromosome 7 and the dihydropteroate reductase (dhps) on chromosome 8. Our analyses showed that a recent selective sweep occurred for the erythrocyte membrane protein (Pfemp1). Conclusion: Our analyses identified genes under selective drug pressure and balancing selection on protective immune-specific genes. These findings demonstrate the effectiveness of genomics analyses to follow the evolution of malaria parasites and adopt appropriate strategies to eliminate malaria in Côte d’Ivoire.