Malaria ranks among the most significant health threats, alongside human immunodeficiency virus (HIV) and tuberculosis influenza. In 2004, Sudan implemented artesunate combined with sulfadoxine/pyrimethamine (SP) as the primary treatment due to the notable resistance of falciparum to antimalarial drugs. The effectiveness of artemisinin combination therapies depends on both artemisinin and the partner drugs. Changes in the Pfmdr1 gene have been associated with chloroquine resistance in specific Plasmodium falciparum isolates. Variations in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are linked to reduced sensitivity to amodiaquine and lumefantrine. However, the exact impact of these variations on treatment outcomes with artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) remains unclear. Alterations in pfmdr1 are linked to decreased uptake of multiple anti-malarial medications, resulting in diminished intracellular levels. Single nucleotide polymorphisms (SNPs) in pfmdr1 correlate with resistance to aminoquinolines. This article examines the development of CQ resistance in Sudan, along with the evidence regarding the effectiveness of current first-line treatments. The situation in Sudan is compared with trends in other African nations and globally, aiming to clarify potential future outcomes for Sudan. Notably, Northern Sudan has been a key region where the initial signs of drug-resistant malaria parasites were identified in Africa.