The introduction of connected automated vehicles (CAVs) on freeways raises significant challenges, particularly in interactions with human-driven vehicles, impacting traffic flow and safety. This study employs traffic microsimulation and surrogate safety assessment measures software to delve into CAV–human driver interactions, estimating potential conflicts. While previous research acknowledges that human drivers adjust their behavior when sharing the road with CAVs, the underlying reasons and the extent of associated risks are not fully understood yet. The study focuses on how CAV presence can diminish conflicts, employing surrogate safety measures and real-world mixed traffic data, and assesses the safety and performance of freeway interchange configurations in Italy and the US across diverse urban contexts. This research proposes tools for optimizing urban layouts to minimize conflicts in mixed traffic environments. Results reveal that adding auxiliary lanes enhances safety, particularly for CAVs and rear-end collisions. Along interchange ramps, an exclusive CAV stream performs similarly to human-driven ones in terms of longitudinal conflicts, but mixed traffic flows, consisting of both CAVs and human-driven vehicles, may result in more conflicts. Notably, when CAVs follow human-driven vehicles in near-identical conditions, more conflicts arise, emphasizing the complexity of CAV integration and the need for careful safety measures and roadway design considerations.