Infectious diseases remain a major global health challenge, causing significant morbidity and mortality. Beyond antimicrobial resistance, challenges in infection management include the immense diversity of pathogens, their ability to persist in latent forms, and the complexity of host–pathogen interactions that allow pathogens to evade immune defences. The ability of pathogens to invade, colonize, and manipulate host systems is governed by complex molecular mechanisms that are often finely tuned to evade host defences. In this study, we examined key molecular pathways involved in host–pathogen interactions, focusing on factors that contribute to pathogen survival, replication, and immune evasion. Using a combination of cellular models, molecular assays, and biochemical analyses, we identified critical virulence factors and host signalling pathways that represent potential intervention points. Structure–activity relationship (SAR) analyses and computer aided drug design (CADD)-based approaches were employed to identify molecular features crucial for pathogen survival and for designing targeted therapeutics. We discuss conventional approaches, such as antibiotics and antiviral drugs, alongside rational, host-directed strategies that modulate immune responses to improve treatment outcomes. Recent developments in antimicrobial therapy, including small-molecule inhibitors, antimicrobial peptides, and biologics, are highlighted, with a perspective on emerging technologies. By integrating mechanistic understanding with translational approaches, this work highlights the importance of a multilevel perspective on infection biology, encompassing molecular, cellular, and organismal responses. These findings provide a context for designing precise and effective interventions, offering potential pathways for improved management of infectious diseases and reduced treatment-related side effects.