Background <p>Gynecological cancers represent a major public health problem in resource-limited settings, where diagnostic delays and limited access to oncology care can worsen clinical outcomes. In Djibouti, data on health-related quality of life (HRQoL) among women with gynecological cancers remain scarce. This study aimed to assess HRQoL using the SF-36 and to explore factors associated with physical and mental scores.</p> Methods <p>A cross-sectional analytical study with prospective data collection was conducted between February and April 2024 in two referral centers in Djibouti. Ninety women with histologically confirmed cervical, endometrial, or ovarian cancer (predominantly cervical cancer) were consecutively included. HRQoL was assessed using the validated French version of the SF-36; bivariate analyses and exploratory multivariate linear regressions were performed.</p> Results <p>The mean age was 54.4 ± 8.9 years; cervical cancer accounted for 85.6% of cases, and 82.2% of patients had advanced disease. HRQoL showed a dissociated profile, with severe physical impairment (mean PCS 33.3 ± 3.2) and a mental component within the normative range (mean MCS 49.4 ± 4.5). In multivariate exploratory analysis, lower PCS was associated with advanced age (<i>p</i> &lt; 0.001), advanced stage (<i>p</i> = 0.014), and ECOG ≥ 2 (<i>p</i> = 0.005). In the MCS model, advanced stage (<i>p</i> &lt; 0.001) and severe pain (<i>p</i> = 0.004) showed positive associations, a counterintuitive finding that should be interpreted cautiously.</p> Conclusion <p>In our sample, Djiboutian women with gynecological cancers experienced substantial physical impairment in HRQoL, while the mental component appeared relatively preserved. These results underscore the need for earlier diagnosis, better pain management, supportive care, and systematic integration of HRQoL into oncological care.</p>