Human papillomavirus (HPV) vaccination has revolutionized cervical cancer prevention. Clinical trials confirm that the quadrivalent (HPV types 6, 11, 16, 18) and bivalent (HPV types 16, 18) vaccines effectively prevent HPV infections and cervical neoplasia. The latest HPV vaccine protects against nine virus types responsible for 90% of cervical cancer cases globally. Despite their undoubted effectiveness in reducing morbidity and mortality associated with HPV infections, challenges in vaccine coverage and uptake persist. The current study aimed to identify the primary challenges associated with HPV vaccination, propose effective strategies to improve vaccination uptake, and compile relevant evidence into a comprehensive overview to inform policy and practice. A systematic review protocol, following PRISMA-P and PRISMA guidelines, was established. Articles were sourced from the Web of Science using keywords from a comprehensive review of HPV vaccination challenges and strategies. Studies published between 1 January 2020, and 1 May 2024, including RCTs and observational, qualitative, and cross-sectional studies, were included, while reviews, protocols, and commentaries were excluded. Titles, abstracts, and full texts were screened per PRISMA guidelines. The review identified five key strategies to improve HPV vaccination uptake: parental and school engagement, use of technology and multimedia tools, healthcare providers’ role, multicomponent interventions, and targeted interventions for immigrant groups. This review emphasized the need for a multifaceted approach to improving vaccination rates, offering a robust foundation for policy and stakeholder initiatives.