Although recent articles have investigated the use of low-dose olanzapine in different psychiatric conditions, only one study so far has assessed this treatment in 13 girls with anorexia nervosa (AN). Observational naturalistic case-control study aimed at reporting the use and tolerability of low-dose olanzapine in the context of a multidisciplinary hospital intervention for adolescents with AN. Three groups with AN were compared: group 1 was treated with low-dose olanzapine (≤5 mg/day), group 2 with full-dose olanzapine (>5 mg/day), and group 3 (control group) was treated without antipsychotics. Psychopathology was assessed at admission (T0) and discharge (T1) with Eating Disorders Inventory-3 Eating Disorders Risk, Body Uneasiness Test Global Severity Index (BUT-GSI), Beck's Depression Inventory-II (BDI-II), and Self-administered Psychiatric Scales for Children and Adolescents, Depression subtest (SAFA-D). Possible differences among the three groups, concerning clinical and treatment variables, were screened. Then, potential differences of T0-T1 modifications in psychopathological variables among the three treatment groups were assessed with analyses of covariance, corrected for baseline psychopathology and potential confounders, including possible concurrent antidepressants. A total of 118 patients were enrolled ( = 94.1%; mean age = 15.4 ± 1.7 years), including 52 controls, 37 treated with low-dose olanzapine, and 29 with full-dose olanzapine. Low-dose olanzapine was well tolerated and used for a mean of 132.1 (±98.6) days, starting with a dosage of 3.4 (±1.2) mg/day and increasing to a maximum dose of 4.4 (±1.1) mg/day. The multidisciplinary intervention resulted in an improvement of BUT-GSI ( < 0.001), BDI-II ( < 0.001), and SAFA-D ( < 0.001) for the entire sample. Individuals treated with full-dose olanzapine experienced a significantly lower improvement in depressive measures: BDI-II ([2,61] = 12.653,  < 0.001, η = 0.269) and SAFA-D ([2,57] = 7.413,  = 0.001, η = 0.170), than the other groups. This naturalistic controlled study expands the existing evidence on the use and tolerability of low-dose olanzapine in adolescents with AN. These results should be assessed in wider and prospective samples.