Malaria is an infectious disease caused by Plasmodium species and transmitted through infected female Anopheles mosquitoes. Malaria is a severe public health issue in sub-Saharan Africa, primarily affecting children and pregnant women, with high global rates of morbidity and mortality. Plasmodium falciparum is the human malaria parasite with the highest virulence, causing most malaria-related deaths. It is estimated that over 500,000 people die from malaria each year. In 2022, the World Health Organization (WHO) reported 249 million cases of malaria prevalence globally in 85 malaria-endemic countries. Additionally, in sub-Saharan Africa, children under the age of 5 account for more than 94% of deaths related to malaria. The severity of Plasmodium falciparum infection is usually exacerbated through multiple invasions and destruction of red blood cells, leading to various symptoms and complications. Currently, the common antimalarial drugs, including artemisinin derivatives, quinoline derivatives, and folic acid antagonists, have been reported to have low efficacy due to various resistance from the parasite. Antimalarial drug resistance emerged from genetic mutations that confer reduced susceptibility of the parasites to antimalarial therapy. Variations in gene copy numbers or single nucleotide polymorphisms are linked to a decline in the susceptibility of parasites to different antimalarial drugs. Recently, the emergence of co-expression of pfcrt and pfmdr1 among symptomatic children below the age of 5 in sub-Saharan Africa has garnered attention because of the increasing morbidity and mortality. The mutant isoforms of Pfmdr1 and Pfcrt alter drug distribution within the parasite, impacting drug access to their targets and leading to high-level multidrug resistance. The incidence of mutant Pfmdr1 and Pfcrt genotypes among children calls for geno-surveillance and genetic testing to prevent poor treatment outcomes. The co-expression of pfcrt and pfmdr1 genes poses significant challenges to malaria control efforts and provides crucial information on their resistance mechanisms to multiple antimalarial drugs, including artemisinin-based combination therapies (ACTs).