Background: Malaria continues to pose significant health challenges globally, with Plasmodium falciparum being the most virulent species contributing to severe complications. This study aims to evaluate the biochemical manifestations of P. falciparum malaria in a tertiary care hospital setting. Materials and methods: A hospital-based cross-sectional study was conducted to assess the biochemical profile of patients diagnosed with P. falciparum malaria. Patients above 12 years of age presenting with fever and confirmed positive for P. falciparum on peripheral smear were included. Patients with comorbid conditions or other identifiable causes of fever were excluded from the study. Results: Among 962 patients admitted for febrile illness, 100 met the inclusion criteria. The most common clinical feature observed was chills and rigors (82%), followed by headache (42%) and vomiting (36%). Complications included cerebral malaria in 38% of patients, severe anemia (10%), oliguria (26%), acute respiratory distress syndrome (1%), hypoglycemia (8%), shock (12%), bleeding manifestations (4%), generalized tonic−clonic seizure (6%), hemoglobinuria (11%), hyperparasitemia (80%), hyperpyrexia (42%), and jaundice (24%). Conclusion: Plasmodium falciparum malaria presents with a diverse biochemical and clinical spectrum, often leading to multiorgan dysfunction. Early recognition and prompt management are essential, and malaria should be considered in patients presenting with febrile illness and systemic complications. This study underscores the importance of vigilant diagnostic approaches in endemic regions.