Objectives Adolescent Sexual and Reproductive Health encompasses their physical and emotional well-being, including their ability to avoid unwanted pregnancies, unsafe abortions, sexually transmitted infections (STIs) and any type of sexual violence and coercion. However, these risks may be mitigated through improved knowledge, encouraging positive attitudes, and adopting better practices. This study aimed to identify the factors associated with knowledge, attitudes and practices (KAP) related to HIV, STI, family planning and pregnancy among adolescents residing in rural Thatta. Design A cross-sectional study. Setting 62 villages from Thatta, Gharo and Jungshahi registered under the Global Network Maternal and Newborn Health Registry in Thatta, Pakistan. Participants 632 adolescents aged 14-19 years. Outcome measures The association between sociodemographic factors and KAP was assessed using a modified version of the 'Asking Young People about Sexual and Reproductive Behaviors' tool. Statistical analysis was performed on Stata V.15.0 using multiple linear regression. Results Among 632 adolescents, 82.7% were females. No significant differences were found in mean scores of knowledge and attitudes between males and females. However, a difference of 0.13 (95% CI 0.005, 0.24) in practice scores was observed. In design-based multivariable analysis, adolescents' marital status (beta 5.13; 95% CI 1.34, 8.91) and father's occupation (beta 3.41; 95% CI 0.90, 5.93) were associated with knowledge. Marital status (beta 1.34; 95% CI 0.82, 1.86), household income (beta -2.36; 95% CI -4.64, -0.07), father's occupation (beta -1.42; 95% CI -2.52, -0.33) and mother's education (beta -1.41; 95% CI -2.71, -0.11) were associated with attitudes. Moreover, marital status (beta 0.24; 95% CI 0.06, 0.41) and mother's occupation (beta 0.64; 95% CI 0.38, 0.90) were associated with practices. Conclusion No differences in knowledge and attitudes between male and female adolescents were found. These findings suggest that community awareness programmes should be implemented to improve sexual and reproductive health KAP for both male and female adolescents in Thatta.