Normal aging is associated with neuronal loss in the dopaminergic midbrain (substantia nigra/ventral tegmental area, SN/VTA), a region that has recently been implicated in processing novel stimuli as part of a mesolimbic network including the hippocampus. Here, we quantified age-related structural degeneration of the mesolimbic system using magnetization transfer ratio (MTR) and correlated it with mesolimbic hemodynamic responses (HRs) to stimulus novelty. Twenty-one healthy older adults between 55 and 77 years performed a visual oddball paradigm allowing to distinguish mesolimbic HRs to novelty from rareness, negative emotional valence, and targetness using functional magnetic resonance imaging. The HRs in the right SN/VTA and the right hippocampus to novelty were positively correlated both with the SN/VTA MTR and hippocampus MTR but not amygdala MTR. However, the HR of the amygdala to negative emotional valence correlated with the amygdala MTR but not with the MTR in SN/VTA or the hippocampus. The results establish a structure-function relationship in support of a hippocampal-SN/VTA loop of mesolimbic novelty processing by showing that the hemodynamic activation in SN/VTA and hippocampus for novelty is selectively affected by age-related degeneration of these structures.