Malaria has been a highly fatal disease for many decades, especially in emerging countries. When we look back and see the drugs that have already been on the market to kill parasites, there are not many new drugs that have been recently introduced by the various pharmaceutical companies. The drugs that are on the market have already been around for quite some time and have their own pros and cons. Most of these drugs have been consistently exhibiting a common problem of poor oral bioavailability, which is moreover dependent on their poor aqueous solubility and/or first-pass effect. Hence, this research work was focused on the assessment of equilibrium solubilities of various anti-malarial drugs (already on the market), especially those drugs that bear a wide range of C log P values. These anti-malarial drugs sourced from different manufacturers (i.e., artemisinin, amodiaquine, halofantrine, and chloroquine) are highly lipophilic in nature and have the least affinity for polar solvents like water, because of which they are least soluble in aqueous media and solvents. The absorption of drugs through the oral route is due to their limited aqueous solubility, which, in the absorption process, becomes a rate-limiting step. The study evaluates the equilibrium solubilities of anti-malarial drugs across a wider physiological range of pH, i.e., in the acidic region pH ~1, ~2, and ~4.5, in the neutral range pH~6.8, and in the alkaline range pH ~7.4, including simulated fasted-state gastric fluid, simulated fasted-state intestinal, simulated fed-state gastric fluid, simulated fed-state intestinal fluid, lipolytic digestive medium, and purified water. The study was conducted as per the shake flask method at 37 °C, and the results concluded that the drug(s) equilibrium solubility was observed to be relatively low in purified water when compared to other physiological pH media. The drug(s) exhibited the highest equilibrium solubility in the simulated GIT dissolution medium. The study indicated that such anti-malarial drugs, which bear higher C Log P values, also tend to solubilize or exhibit higher solubility in the presence of gastric, intestinal, and lipoidal media because the drug undergoes solubilization under the available surfactants present in the medium, e.g., sodium taurocholate and/or likewise. All model drugs exhibited a similar trend and solubilization effect, which indicated the potential of lipid-based drug delivery systems as one of the most preferred delivery systems