The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) for treatment of falciparum malaria. Arteether (ART), an artemisinin derivative, is effective against Plasmodium falciparum, but it is available only as painful oily intramuscular (i.m.) injections. We formulated lyotropic liquid crystalline preconcentrates of ART and Lumefantrine (LUM) ACT with and without biodegradable polymer for antimalarial therapy. Following i.m. injection, both formed intact gels in situ due to rapid transition into liquid crystalline phase (LCP) which was confirmed by small angle neutron scattering (SANS), X-ray diffraction (XRD), polarization optical microscopy (POM) and rheological changes. Ex vivo release studies revealed prolong release of ART-LUM over 72 h from polymeric lyotropic liquid crystalline phases (P-LLCPr). In vitro hemolysis assay and myotoxicity studies confirmed intramuscular safety. Treatment with ART–LUM P-LLCPr conferred complete protection with no mortality at 1/40th of therapeutic dose in modified Peter’s four-day suppressive test as compared to marketed ART formulation resulted in 100% mortality within 20 days. In the clinical simulation model, P-LLCPr treatment resulted in complete cure with no recrudescence or mortality at 1/20th of therapeutic dose, while marketed formulation which resulted in 100% mortality. The high efficacy with significantly reduced dose and a single administration with single shot therapy suggest ART-LUM P-LLCPr as a promising new patient friendly alternative for antimalarial therapy.