Background/Objectives: Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have transformed cancer treatment, yet therapeutic responses remain limited in many solid tumors due to poor and uneven drug distribution within the tumor microenvironment (TME). Here, we evaluated whether co-formulation of an anti-PD-1 antibody (RMP1-14, murine surrogate for pembrolizumab) with Imagent^® microbubble/liposome (MBLP) complexes and ultrasound activation could enhance tumor-specific delivery while reducing systemic exposure. Methods: Immunocompetent MC-38 colorectal tumor-bearing mice (B6(Cg)-Tyrc-2J/J, 7-week-old females) received isotype control, isotype/MBLP/US, RMP1-14 alone, RMP1-14/MBLP, or RMP1-14/MBLP/US. Survival was analyzed by Kaplan–Meier curves, tumor necrosis by H&E staining, antibody biodistribution by immunohistochemistry, and tumor perfusion by laser speckle imaging. Results: No significant differences in tumor size or body weight were observed between groups. Survival analysis showed significant improvements in the RMP1-14 (p = 0.013) and RMP1-14/MBLP/US (p = 0.047) groups versus isotype controls, with the RMP1-14/MBLP/US group achieving the longest mean survival (57.8 days vs. 26.5 days for RMP1-14 alone) and complete tumor regression in 2/8 mice. The RMP1-14/MBLP/US group demonstrated significantly greater tumor necrosis than all other groups. Immunohistochemical analysis confirmed a 6.1-fold increase in intratumoral antibody accumulation with MBLP/US versus RMP1-14 alone (p = 0.0003), alongside significantly reduced off-target exposure in spleen, liver, kidney, and heart. Laser speckle imaging revealed a transient ~30% increase in tumor perfusion during MBLP/US treatment, consistent with cavitation-mediated hemodynamic effects. Conclusions: These findings demonstrate that MBLP/US co-formulation enhances intratumoral delivery of checkpoint inhibitors, improves survival, and reduces systemic organ exposure, representing a promising platform to improve the efficacy and safety profile of antibody-based immunotherapy.