**Abstract**

Malaria is a complex disease associated with a variety of epidemiology and clinical symptoms worldwide. Despite the availability of a variety of antimalarial medications, national policies of many countries advocate for a single-medication first-line therapy for the majority of clinical malaria symptoms. However, the studies revealed that using multiple first-line medicines against malaria works more effectively. In this scenario, single-target monotherapy approaches have difficulties since malaria symptoms are seldom caused by single molecular entities. The current work is based on the critical literature review and primary sources as well as secondary databases. The chapter outline is as follows: (1) main antimalarial plant-derived active pharmaceutical ingredients (APD-APIs), (2) limitations of single APD-APIs and shift to multiple first-line therapies in malaria treatment, (3) techniques in the development and properties of APD-APIs co-crystals. The search for novel plant-derived antimalarial medicines and the development of antimalarial co-crystals are essential in the fight against antimalarial drug resistance.

**Keywords:** antimalarial drugs, mono-therapy, multiple first-line treatments, co-crystallization, plant-derived antimalarial drugs
