Background: Adult acute lymphoblastic leukemia (ALL) patients are at increased risk of invasive fungal infections (IFIs) due to intensive therapy and prolonged neutropenia. While pediatric guidelines support administering fluconazole or mold-active agents, the evidence in adults is limited. This study presents the first multicenter retrospective comparison of fluconazole and micafungin use in this setting. Methods: We retrospectively analyzed 336 adult ALL patients from 11 centers in Türkiye (2010–2024) who received fluconazole (n = 230) or micafungin (n = 106) during induction chemotherapy. IFIs were classified according to the EORTC/MSG criteria. Results: The median age was 38.5 years, and 38.7% were female. Proven/probable IFIs occurred in 8.9% of patients, with similar rates between the fluconazole and micafungin groups (8.7% vs. 9.4%; p = 0.82). Multivariate analysis confirmed no significant association between the prophylactic antifungal type and IFI incidence, indicating comparable outcomes across groups. The median prophylaxis duration was longer with fluconazole, while the discontinuation rates, switch patterns, and subsequent antifungal use were comparable. The overall infection rates (~60%) and distribution of bacterial, viral, and polymicrobial infections were similar between the two groups. Prior bacterial infection increased the risk of IFI by 2.7-fold, and IFI-positive patients had longer neutropenia. At the end of induction, the remission, refractory, and mortality rates were similar between groups. The median overall survival was 24 months. Conclusions: Fluconazole and micafungin showed similar efficacy as the primary antifungal prophylaxis treatment in adult ALL patients. Given the limited evidence in adults and the ongoing need to optimize antifungal strategies, prospective randomized trials directly comparing these agents in this population are needed to confirm and expand upon our findings.