The success of COVID-19 vaccination programs depends on public acceptance, yet evidence from southern Libya remains limited. This study aimed to examine public perceptions, attitudes, and willingness toward COVID-19 vaccination among adults in urban and rural areas of southern Libya. A cross-sectional survey of adults in Sebha and the surrounding areas was conducted. Data were analysed using descriptive statistics and chi-square tests. A total of 785 questionnaires were distributed, of which 689 were completed and returned, yielding a response rate of 87.8%. The internet was the most commonly reported source of information about COVID-19 vaccination (58.2%), followed by television (25.4%). Overall, 64.6% of participants expressed willingness to receive the COVID-19 vaccine, while 35.4% were unwilling. Vaccine willingness was significantly associated with age group, marital status, place of residence, and education level. The most common reasons for acceptance were protection against COVID-19 infection (33.0%), free vaccine availability (20.0%), and prevention of transmission to others (15.8%). Among those who refused, the leading reason was concern about vaccine safety and/or side effects (50.0%), followed by preference to wait and observe effects in others (14.3%), doubts about effectiveness (10.3%), and general vaccine distrust (9.9%). Regarding opinions, 50.4% agreed that COVID-19 vaccination was important, 50.9% agreed that everyone should receive the vaccine once it is available, and 37.3% supported mandatory vaccination. This study reveals moderate willingness to receive COVID-19 vaccines among adults in southern Libya, with safety concerns and mistrust as key barriers. Targeted campaigns that engage healthcare professionals and counter misinformation are urgently needed. Importantly, these barriers extend beyond COVID-19, affecting routine and future vaccinations. Given Libya's fragile health system, these efforts must be integrated into a comprehensive national immunization plan to build sustainable vaccine confidence and resilience in the health system.