Religion is a notable psychosocial factor that influences vaccination decision-making behavior; understanding the role of religious factors in Human Papillomavirus (HPV) vaccine uptake is crucial. This cross-sectional study examines the relationship between religiosity and HPV vaccine uptake among Indiana adults (ages 18-45 years) and investigates whether vaccination confidence mediates this relationship. Religiosity was measured by examining the frequency of attendance at religious meetings on a scale of 1 (never) to 6 (>1/week), then grouped into 3 categories (low, middle, high). A mean score of HPV vaccination confidence was measured using nine items and vaccine uptake used a binary (yes/no) categorization if the person had ever received any vaccines. We used multivariable logistic regression to analyze the association between religiosity, sociodemographic factors, and HPV vaccination uptake. We conducted a Structural Equation Modelling (SEM) mediation analysis to assess the indirect, direct, and total effects of religiosity on HPV vaccine uptake, with vaccination confidence as a potential mediator. Most of our sample were women (n=160, 52.6%), religiously affiliated (n=157, 51.6%), and had never received the HPV vaccine (n=160, 52.6%). We found that higher religiosity (aOR=2.76, 95% CI:1.15-6.62) and vaccination confidence (aOR=3.13, 95% CI:2.06-4.77) were associated with increased odds of HPV vaccine uptake, while being older (aOR=0.91, 95% CI: 0.87-0.95) or being male (aOR=0.50, 95% CI: 0.28-0.91) were associated with decreased odds of HPV vaccine uptake. The indirect effect of religiosity on HPV vaccine uptake through HPV vaccination confidence was not significant while the direct effect was significant, indicating no mediation effect. Future studies should explore other potential mediators and develop targeted interventions to increase vaccine uptake among populations with varying levels of religiosity.