Experimental evolution in vivo is a powerful approach to identify the selective pressures shaping bacterial adaptation during infection, yet how host immunity modulates these evolutionary trajectories remains a fundamental gap in infection biology. Applying whole-population genomic sequencing to replicate bacterial populations serially passaged through murine or porcine infection models, we demonstrate that niche-specific selective pressures produce convergent genetic adaptations, including parallel mutations modulating pneumococcal surface charge during colonization and prophage-mediated disruption of global regulators during chronic Pseudomonas aeruginosa wound infection. Host immune status critically shapes these trajectories, as neutropenic hosts broaden mutational pathways to fluoroquinolone resistance in Acinetobacter baumannii while functional immunity constrains the outgrowth of resistant variants. Most recently, we show that Streptococcus pneumoniae subjected to combined antibiotic and immune pressure evolves convergent mutations altering the RNA degradosome that confer broad-spectrum antibiotic tolerance through a bet-hedging transcriptional strategy influenced by host immune state. Together, these studies establish that in vivo experimental evolution provides a mechanistic roadmap for predicting genetic pathways to treatment failure and informing strategies to constrain the evolution of antimicrobial resistance.