Aim: This study aimed to evaluate and compare the clinical profiles of patients with Plasmodium falciparum, Plasmodium vivax, and mixed malaria infections, focusing on demographic characteristics, clinical symptoms, laboratory findings, and complications to enhance diagnosis and treatment strategies. Material and Methods: An observational, cross-sectional study was conducted at a tertiary care hospital involving 120 patients with confirmed malaria diagnoses. Participants were categorized into three groups: P. falciparum (Group A), P. vivax (Group B), and mixed infections (Group C). Clinical and laboratory data were collected, including hematological and biochemical parameters, parasitemia levels, and complication frequencies. Statistical analyses, including ANOVA and chi-square tests, were performed to identify significant differences among the groups. Results: Mixed infections exhibited the highest severity with prolonged hospital stays (5.6 ± 2.0 days), lower hemoglobin levels (8.7 ± 1.3 g/dL), and elevated parasitemia levels (28,300 ± 6,100 parasites/μL) compared to single-species infections. Complications, including severe anemia (35%), thrombocytopenia (60%), and jaundice (40%), were more frequent in mixed infections. P. falciparum showed higher rates of cerebral malaria (10%) and multi-organ dysfunction (15%), while P. vivax had relatively milder presentations. Conclusion: Mixed malaria infections present the most severe clinical profiles compared to single-species infections, emphasizing the need for accurate diagnostics and prompt treatment. Tailored therapeutic strategies are crucial, particularly in endemic regions where co-infections are prevalent, to improve patient outcomes and reduce malaria-related morbidity.