Antiviral resistance (AVR) in Africa poses clinical and public health challenges across multiple viral pathogens, including HIV, HBV, HCV, influenza, mpox, and SARS-CoV-2, yet comprehensive reviews are sparse, and surveillance varies widely. Thus, this chapter summarises AVR patterns in key viruses across Africa, evaluates current challenges, and proposes strategies for mitigation. To achieve this, peer-reviewed literature, WHO and Africa Centre for Disease Control and Prevention (CDC) reports, and recent surveillance data were synthesised to map resistance trends, highlight clinical and laboratory challenges, and propose a strategic roadmap. Existing literature and data revealed that over the recent decades, antiviral resistance in Africa has emerged as a major public health crisis, threatening to undermine significant progress in the treatment of diseases like HIV, hepatitis, and influenza. The situation is complex, marked by both successes and critical challenges, including limited surveillance, suboptimal treatment adherence, pretreatment resistance, and socioeconomic factors. Addressing these challenges calls for a multifaceted approach involving integrated surveillance, ensuring quality drug delivery, improving patient retention and adherence to treatment, and establishing strategic local and international partnerships.