This study presents a comparative analysis of the host–pathogen protein–protein interactions (PPIs) in HIVHIV and Mycobacterium tuberculosis (MTB)Mycobacterium Tuberculosis (MTB) infections where we focus on the human proteins targeted by these pathogens, focusing on their topological, structural, and functional properties. Although the specific molecular targets differ, both HIV and MTB generally interact with human proteins having high centrality values in the human protein–protein interaction network. HIVHIV primarily targets proteins involved in immune regulation and transcription, essential for its rapid replication and immune evasion. In contrast, MTBMycobacterium Tuberculosis (MTB) interacts with proteins involved in cellular maintenance and metabolic adaptation, which contributes to its long-term persistence in the host. Our analysis highlights the differences in the strategies employed by each pathogen to manipulate host cellular functions and underscores the importance of understanding these interactions for the development of therapeutic strategies against both infections.