Background Kyasanur forest disease (KFD), also known as monkey fever, was first recognized in the Shimoga district of Karnataka, India, in 1957. This study was conceived to address the paucity of medical literature on KFD, to describe the clinical and laboratory features of real-time reverse-transcriptase-polymerase chain reaction (rRT-PCR) confirmed cases of KFD, and to detect any change in the clinical picture and presentation of the disease over the last 30 years. Aim The study sought to document the clinical and laboratory features of Kyasanur forest disease (KFD), a tick-borne arboviral disease, now emerging in many parts of southern India. Material and methods This was a retrospective study using secondary data of patients with real-time reverse transcription-polymerase chain reaction (rRT-PCR)-confirmed KFD in a secondary care hospital in Wayanad, Kerala, India. Results Sixty rRT-PCR-proven KFD patients were included in the study. Commonly noted clinical symptoms were fever (98%), headache (80%), body ache (86%), vomiting (61%), and prostration (83%). Relative bradycardia, hypotension (45%), and oral lesions (23%) were the frequent physical signs. The median total leukocyte count and median platelet count at admission were 2600 per μL and 1.62 per μL, respectively. The median erythrocyte sedimentation rate was 10 mm/hr. Urinary sediments and albuminuria were seen in 66% and 60% respectively. The major complications observed were neurological complications (23%), bleeding manifestations (20%), and persistent shock (20%). The common neurological complications were seizures, altered sensorium, aseptic meningitis, and focal neurological deficits. The case fatality rate in the study was 6.7%. Conclusions The clinical picture of a prostrating viral syndrome in an epidemiological setting of KFD with marked leucopenia, moderate thrombocytopenia, low erythrocyte sedimentation rate (ESR), albuminuria, urinary sediments, and moderately elevated transaminases help in making an early diagnosis of KFD. Neurological complications in the initial two weeks are associated with poor outcomes.