<p>The objective of this study was to understand key genes and molecular processes that are supposedly involved in the transmission of Cotton leaf curl virus (CLCuV) by its vector whitefly, <i>Bemisia tabaci</i>, considering its midgut proteins and its endosymbionts. Two midgut proteins were selected based on their participation in virus transmission: thioredoxin-like protein (Accession no. AQM74407) and cytochrome oxidase subunit I (Accession no. AFQ62605). Furthermore, the GroEL protein of the primary endosymbiont <i>Candidatus portiera aleyrodidarum</i> was considered for the study to assess interactions with viral particles. Protein–protein interaction networks were constructed and subjected to functional enrichment analyses utilizing GO and KEGG database analysis to establish the important genes and biological pathways involved. Network clustering revealed functionally enriched subnetworks linked with virus transmission. The hub genes identified from these analyses were involved in various biological processes such as protein folding, stress response, and membrane transport, all of which may assist in helping the virus survive and translocate in the insect vector. GroEL-related subnetworks exhibited strong relationships with viral coat proteins which may suggest that GroEL provides some protective function during transit through hemolymph. This study contributes significantly to a new understanding of the highly complex relationship between the insect vector, endosymbionts, and plant viruses. These findings will therefore add to the understanding of the transmission of CLCuV and may be useful in designing virus control interventions for crop protection.</p>