Psychological adjustment significantly impacts the well-being of young individuals diagnosed with cancer. However, limited research examines the roles of self-esteem and social support, particularly with gender and age as potential moderators and mediators in low-resource settings like Uganda. This study investigated these relationships to inform gender-sensitive psychosocial interventions. Using a correlational research design, 98 participants aged 18–30 were recruited from cancer treatment centers in Uganda through multistage sampling. Data were collected using the Psychological Adjustment to Illness Scale, the Multidimensional Scale of Perceived Social Support, and Rosenberg’s Self-Esteem Scale, all demonstrating strong reliability (Cronbach’s α > 0.80). Analysis involved path modeling and conditional process analysis with SPSS and JASP software. The result showed that self-esteem (β = 0.814, p < .001) and social support (β = 1.120, p < .001) significantly predicted better psychological adjustment. Gender moderated these relationships, with males benefiting more from self-esteem and social support than females. Age did not mediate the effects of social support or self-esteem on psychological adjustment. These results emphasize the importance of self-esteem and social support in enhancing psychological adjustment while highlighting gender disparities in their impact. The findings underscore the need for gender-sensitive psychosocial support programs. Interventions should bolster self-esteem and foster social support for males while addressing systemic barriers affecting females. Policymakers should allocate resources to ensure equitable access to mental health support for young cancer patients.