This study assessed the determinants that shape HIV knowledge and attitudes among South Sudanese women by analysing a Multiple Indicator Cluster Survey collected from 9,061 women in 9,369 households. Generalised linear mixed model regression was performed. Fifty percent of respondents were aware of HIV/AIDS, with 21% and 22% exhibiting good knowledge and positive attitudes towards people with HIV/AIDS, respectively. When controlled for individual and community-level variables, younger women (AOR = 1.28, 95% CI: 1.01–162), women with primary (AOR = 2.19; 95% CI: 1.86–2.58) and secondary (AOR = 4.48; 95% CI: 3.38–5.93) education, and those living in urban areas (AOR = 1.40; 95% CI: 1.12–1.76) had significantly good knowledge. Women in the richer (AOR = 1.60; 95% CI: 1.08–2.36) and the richest (AOR = 2.02; 95% CI: 1.35–3.02) wealth quintiles had significant positive attitudes towards people with HIV/AIDS. Well-designed social and behavioural campaigns targeting uneducated women and those living in rural and remote settings will enhance knowledge of perceived risk, awareness, and ability to carry out preventive behaviours.