Background Pre-emptive antifungal therapy in neutropenic fever offers a rational alternative to the empiric strategy, potentially reducing drug toxicity, resistance, and treatment-related costs. However, its implementation in the Middle East and North Africa (MENA) region remains insufficiently addressed. Methods We prospectively observed episodes of neutropenia in Pediatric patients with solid tumors and prolonged neutropenia. This non-inferiority cohort study evaluated three primary endpoints: the cumulative incidence of invasive fungal infection (IFI), IFI-attributable mortality, and the rate of antifungal use. Outcomes from the prospective cohort managed with a pre-emptive strategy were compared with retrospective data from a historical cohort treated with the previously used empiric approach. Results A total of 422 pre-emptive episodes were prospectively recorded, and data from 338 historical empiric episodes were retrospectively reviewed. The incidence of IFI was comparable between the two groups (4·5% in the pre-emptive group vs 5·6% in the empiric group; p = 0·5). However, antifungal use was significantly lower in the pre-emptive group (5·0% vs 58·0%; p < 0·001). Overall survival was higher in the pre-emptive group (98·9% vs 94·6%). No IFI-attributable mortality was recorded in either group. Interpretation The combined EIA/HRCT-based pre-emptive strategy is feasible and associated with reduced antifungal use without compromising patient outcomes in Pediatric patients with solid tumors and prolonged neutropenia.