Cattle theileriosis is infamous for hampering the economic development of south, central and east African countries due to the exorbitant numbers of cattle mortalities. The disease is caused by Theileria parva, a tick-transmitted hemoprotozoan parasite belonging to the phylum Apicomplexa. Infection of cattle with the cattle-derived T. parva isolates is responsible for the East Coast fever while infections by buffalo-derived isolates result in the Corridor disease. A transcriptome study comparing two T. parva isolates, representing cattle- and buffalo-derived parasites, identified several differentially expressed transcripts, of which 54.4% encode hypothetical proteins (HPs). These proteins are believed to be crucial in understanding the disease syndromes caused by T. parva infections; hence, the purpose of this study was to annotate their function. The 309 proteins analysed in this study exclude HPs that were assigned sequence descriptions and had pathway associations with initial screenings using Blast2GO and KEGG pathway analyses. For function prediction, an integrated bioinformatics approach was employed which facilitated sequence comparison, protein family classification, domains discovery, sub-cellular localisation, protein-protein interactions and identification of virulence factors. Overall, 277 (90%) HPs were successfully annotated for function with 224 of these being possible virulent proteins. Enzymes, membrane-associated proteins, transcription factors and secreted proteins, were some of the protein families detected among the HPs. Secretome analysis revealed 57 HPs containing signal peptides, suggesting possible interactions with the host. Thus, among the HPs investigated, there are proteins that could have various functions significant to the pathogenesis of cattle theileriosis including attachment of the pathogen to the host surfaces, disruption of host signal pathways, colonisation of the host cell, immunosuppression, host cell phenotype modulation and proliferation. Sub-cellular localisation revealed three HPs that did not have homologs to any of the vertebrate host proteins, which can be investigated as possible therapeutic targets. The findings of this study will facilitate a better understanding of the mechanism of pathogenesis associated with cattle theileriosis and identification of novel targets to improve disease control strategies. Thus, HPs with predicted biological roles of interest should be further explored experimentally to confirm their roles in cattle theileriosis.