Essential hypothetical proteins (EHPs) derived from essential genes of the pathogenic Francisella tularensis Schu S4 strain have great implications in comparative and functional genomics investigations as these uncharacterized hypothetical proteins impede the search for potential drug targets. The present in silico study emphasized on the physicochemical, functional and structural annotations of the EHPs. 24 out of 44 EHPs were functionally annotated successfully and supported by statistical quality assessment parameters whereas functionality of rest of the EHPs could not be predicted effectively due to the insufficient sequence resemblance in the database. Subcellular localization, virulence factor prediction and non-homology analysis will be effective for host-pathogen interaction study as well as drug/vaccine development. The secondary and tertiary structure prediction provides valuable insights regarding the spatial positioning of amino acids in the proteins to find the potential binding sites for drugs. Therefore in vitro and in vivo experimental studies of these EHPs should be carried out to draw effective conclusions in the rapidly advancing field of drug discovery.