Apolipoprotein D (ApoD) is a member of the lipocalin family which is secreted from subsets of neurons and glial cells. Previously, it has been reported that the expression level of ApoD is strongly up-regulated in the brain of Alzheimer’s disease (AD) patients, and that ApoD has a protective function against oxidative stress in several animal models. However, the role(s) of ApoD in the pathogenesis of AD is still not understood. Here, we demonstrated the role of Glial Lazarillo (GLaz), a gene for a Drosophila ApoD homolog, in the AD-like phenotypes of Aβ42-expressing flies. GLaz overexpression mitigated the Aβ42-induced phenotypes such as rough eyes, locomotive defect, reduced survivability and neuronal cell death. In addition, increased ROS level and sensitivity to oxidative stress in the AD model flies were significantly reduced by pan-neuronally overexpressed GLaz, without alteration of the amount of Aβ42 accumulations. Taken together, our results suggest that ApoD plays a protective role against the AD-like phenotypes of AD model flies by inhibiting oxidative stress, and that ApoD can be a potential genetic marker and therapeutic target of AD.