Antimicrobial resistance (AMR) presents a growing global threat, driven by widespread antibiotic misuse across human and veterinary medicine. Companion animals, particularly dogs and cats, harbor complex natural microbiota—including skin, mucosal, and gastrointestinal communities—that are essential to their health yet also serve as reservoirs of antibiotic resistance genes (ARGs). These ARGs can spread through horizontal gene transfer (HGT), especially during bacterial imbalances such as endogenous infections or surgical interventions, increasing the risk of difficult-to-treat infections. Documented zoonotic and anthroponotic transmissions of resistant strains such as MRSA, MRSP, and ESBL-producing E. coli highlight the bidirectional nature of ARG flow between animals and humans. This underscores the critical importance of the One Health approach, which promotes interdisciplinary collaboration to monitor, understand, and combat AMR across the human–animal-environment interface. Key mechanisms of ARG dissemination, the role of companion animal microbiota, and real-world examples of resistance transfer between species illustrate the complexity and urgency of addressing AMR. Targeted surveillance, rational antibiotic use, and public awareness are essential to preserving antimicrobial efficacy and safeguarding both human and animal populations.