Background: Cervical cancer is the second most common cancer among women in French Guiana. Studies have shown that populations living in isolated inland communities within the department tend to become sexually active at an early age and that having multiple sexual partners is common there. In this context, the main objective of this study was to determine the prevalence of human papillomavirus (HPV) infection in these areas. Methods: This multicenter cross-sectional study was conducted among women aged 20 to 65 years residing in remote communities along the Maroni and Oyapock rivers. Women were included on a voluntary basis after being informed of the study team’s visit via local radio and by community leaders. Testing for HPV infection and cytological analyses were performed on each sample. HPV infection was defined by the detection of viral DNA using the Greiner Bio One® screening kit. Cytological analyses were described according to the 2001 Bethesda classification. Results: A total of 643 women were included. The age-standardized prevalence of HPV infection was 35%. The prevalence curve by age group was U-shaped: women over 50 had the highest risk of HPV infection, followed by women aged 20 to 29. Furthermore, 26.1% of women with a normal Pap smear were infected with HPV. The most common genotypes were HPV52, HPV58, and HPV16. Among interpretable Pap smears, 1.16% of women had high-grade lesions (HSIL). Conclusions: The age-standardized prevalence rate of HPV infection in French Guiana is among the highest in the world. HSIL-type cytological lesions were nearly four times more common than in Île-de-France. Given the high incidence of cervical cancer in French Guiana, these results suggest that it may be preferable to use the HPV test rather than cytology. HPV vaccination, preferably with the new nonavalent vaccine, appears to be an appropriate preventive measure. However, implementing these interventions remains a challenge in this region, where a significant portion of the population lacks health insurance.