Gorakhpur division consisting of Gorakhpur and neighboring districts Deoria, Kushinagar and Maharajganj in Uttar Pradesh, India, have been witnessing seasonal outbreaks of acute encephalitis syndrome (AES) among children for the last three decades. Investigations conducted during 2005 identified Japanese encephalitis (JE) virus as an aetiology of AES. With the introduction of JE vaccination and other control strategies, the incidence of JE in the region declined, however, outbreaks of acute febrile illness with neurological manifestations continued to occur. Subsequent investigations identified Orientia tsutsugamushi, as the major aetiology of AES outbreaks in the region. This review details clinical, epidemiological, animal and entomological investigations conducted for AES due to O. tsutsugamushi during 2015 and 2017 in Gorakhpur region. Surveillance of acute febrile illness among children attending peripheral health facilities identified scrub typhus as an important aetiology of febrile illness during monsoon and post-monsoon months. Population-based serosurveys indicated high endemicity of scrub typhus. Entomological studies demonstrated natural infection of O. tsutsugamushi in small animal hosts and vector mites. Children acquired this infection through recent exposure to outdoor environment, while playing, or visiting fields or defecating in open fields. A few of the children with scrub typhus progress to develop CNS manifestations. Hence, early administration of appropriate antibiotics is crucial in preventing progression of AFI due to scrub typhus to AES. The investigations conducted by the multi-disciplinary team helped understand the transmission dynamics of scrub typhus in Gorakhpur division and recommend strategies for its control.