Acute encephalitis syndrome (AES) refers to an acute onset of fever and clinical neurological manifestation that includes mental confusion, disorientation, delirium, or coma, which may occur because of infectious or non-infectious causes. Cerebrospinal fluid (CSF) pleocytosis generally favors infectious etiology, and a normal CSF favors an encephalopathy or non-infectious AES. Among the infectious AES, viral, bacterial, rickettsial, fungal, and parasitic causes are the commonest. Geographical and seasonal clustering and other epidemiological characteristics are important in clinical decision making. Clinical markers like eschar, skin rash, myalgia, hepatosplenomegaly, thrombocytopenia, liver and kidney dysfunction, elevated serum CK, fronto-temporal or thalamic involvement on MRI, and anterior horn cell involvement are invaluable clues for the etiological diagnosis. Categorizing the AES cases into neurologic [Herpes simplex encephalitis (HSE), Japanese encephalitis (JE), and West Nile encephalitis (WNE)] and systemic (scrub typhus, malaria, dengue, and Chikungunya) helps in rational utilization of diagnostic and management resources. In neurological AES, cranial CT/MRI revealing frontotemporal lesion is consistent with HSE, and thalamic and basal ganglia lesions are consistent with JE. Cerebrospinal fluid nucleic acid detection test or IgM antibody for JE and HSE are confirmatory. Presence of frontotemporal involvement on MRI indicates acyclovir treatment pending virological confirmation. In systemic AES, CT/MRI, PCR for HSE and JE, and acyclovir therapy may not be useful, rather treatable etiologies such as malaria, scrub typhus, and leptospirosis should be looked for. If smear or antigen for malaria is positive, should receive antimalarial, if negative doxycycline and ceftriaxone should be started pending serological confirmation of scrub typhus, leptospira, or dengue. A syndromic approach of AES based on the prevalent infection in a geographical region may be developed, which may be cost-effective.