Background The effectiveness of mental health interventions such as trauma‐focused cognitive behavioral therapy (TF‐CBT) may vary by client, caregiver, and intervention‐level variables, but few randomized trials in low‐ and middle‐income countries (LMIC) have conducted moderation analyses to investigate these characteristics. This study explores moderating factors to TF‐CBT treatment response among a sample of orphans and vulnerable children (OVC) in Zambia. Methods Data were obtained from a completed randomized trial of TF‐CBT among 257 OVC in Zambia. Trauma symptoms and functioning were measured at baseline and following the end of treatment. Mixed effects regression models were estimated for each moderator of interest: gender, age, number of trauma types experienced, history of sexual abuse, orphan status, primary caretaker, school status, and parental involvement in treatment. Results Treatment effectiveness was moderated by history of sexual abuse with greater reductions in both outcomes (trauma, p < .05; functioning, p < .01) for those that experienced sexual abuse. Primary caretaker was also a moderator with greater trauma reductions in those who identified their mother as the primary caretaker (p < .01), and better functioning in those that identified their father as the primary caretaker (p < .05). Nonorphans and single orphans (mother alive) showed greater reduction in functional impairment (p < .01) compared with double orphans. There was no significant moderator effect found by gender, age, number of trauma types, school status, or caregiver participation in treatment. Conclusions This study suggests that TF‐CBT was effective in reducing trauma symptoms and functional impairment among trauma‐affected youth overall and that it may be particularly effective for survivors of child sexual abuse and children whose primary caretaker is a biological parent. Scale‐up of TF‐CBT is warranted given the wide range of effectiveness and prevalence of child sexual abuse. Future randomized trials of interventions in LMIC should power for moderation analyses in the study design phase when feasible.