The human papillomavirus (HPV) vaccine is a critical public health measure designed to reduce the incidence of HPV-related cancers, particularly cervical cancer. Despite its proven efficacy, vaccine uptake remains suboptimal in many areas, including Korogocho ward, a densely populated informal settlement in Nairobi County, Kenya. This study explored factors influencing HPV vaccine uptake among girls aged 9–14 in Korogocho. A total of 812 caretakers participated, identified through snowball sampling during the baseline survey of the Health Awareness, Learning and Education (HEALEDUC) intervention. The HEALEDUC initiative, a quasi-experimental study, employed intervention and control groups with pre- and post-intervention assessments to evaluate strategies for improving HPV vaccination rates in the region. Key findings revealed that caretaker age significantly impacted vaccination decisions (p = 0.022). Caretakers aged 35–44 were more likely to vaccinate their children (OR = 1.930, 95% CI = 0.790–4.716), although no consistent patterns emerged among other age groups. Interestingly, uncertainty about HPV transmission was associated with higher vaccine uptake (OR = 2.024, 95% CI = 1.107–3.701, p = 0.022). Negative perceptions of healthcare workers’ attitudes strongly correlated with increased vaccination likelihood (OR = 4.883, 95% CI = 1.834–12.999, p = 0.002). Satisfaction with healthcare services demonstrated borderline significance (p = 0.059). Conversely, distance to healthcare facilities (p = 0.348) and transport costs (p = 0.873) were not statistically significant determinants of vaccine uptake. However, caretakers residing more than 10 km from healthcare facilities exhibited slightly higher odds of vaccinating their children (OR = 3.136, 95% CI = 0.521–18.881). These findings underscore the importance of targeted interventions to bridge knowledge gaps, foster trust in healthcare systems and improve interactions between caretakers and healthcare providers. Addressing these factors can enhance HPV vaccine uptake in resource-limited settings.