Dopamine (DA) dysregulation has been linked to schizophrenia (SCZ) psychopathology for decades, but there is still an unmet need to identify underlying neural mechanisms. In particular, dopaminergic hyperactivity found in SCZ patients primarily in the associated/dorsomedial striatum (DMS), but not ventral striatum raises the necessity to address the role of the nigrostriatal pathways in SCZ. In order to study DA dysregulation relevant to human disease, we made use of the Df(16)A+/- mouse model of the 22q11.2 Deletion Syndrome, the most common chromosomal microdeletion and the highest genetic risk factor for SCZ. Using chronic in vivo single-unit extracellular recordings of pharmacologically or genetically identified DA neurons we detected persistent electrophysiological hyperactivity in DA substantia nigra (SN) neurons in both male and female Df(16)A+/- mice compared to controls, which was irrespective of locomotor hyperactivity. This was characterized by increased mean firing frequencies and elevated bursting activity. Using dLight1 fluorometry, we detected a higher rate of DA transients in Df(16)A+/- mice in DMS, as would have been predicted by a DA hyperexcitability phenotype, if tightly coupled to striatal DA dynamics. Moreover, we used chemogenetic tagging to selectively measure the activity of the DMS-projecting medial SN DA subpopulation and found enhanced bursting and firing activity in the Df(16)A+/- mice. Assessment of DMS-dependent goal-directed behavior revealed a specific outcome devaluation deficit in the Df(16)A+/- mice, similar to the one observed in schizophrenia patients. Our findings provide strong evidence for an increased nigrostriatal DA function in the Df(16)A+/- mice of both sexes, possibly affecting goal-directed behavior.