Previous research has suggested that individuals with Down syndrome experience specific hippocampal dysfunction which may impair their ability to navigate from one environment to another. One strategy used to enhance spatial navigation is the instruction of prominent landmarks along a path. The current study examined the effects of landmark instruction on wayfinding ability in persons with Down syndrome in comparison to typically developing children of the same mental age and individuals with intellectual disability not resulting from Down syndrome of the same chronological age. The results indicated that the participants with Down syndrome performed significantly worse on the wayfinding task than both the typically developing participants and those with mixed-etiology intellectual disability, despite showing an improvement in performance due to landmark instruction. Future research could examine the direct connection between hippocampal dysfunction and impairment in spatial navigation as well as explore the role of prior experience in wayfinding ability.