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Drugs of abuse induce persistent remodeling of reward circuit function, a process thought to underlie the emergence of drug craving and relapse to drug use. However, how circuit-specific, drug-induced molecular and cellular plasticity can have distributed effects on the mesolimbic dopamine reward system to facilitate relapse to drug use is not fully elucidated. Here, we demonstrate that dopamine receptor D3 (DRD3)-dependent plasticity in the ventral pallidum (VP) drives potentiation of dopamine release in the nucleus accumbens during relapse to cocaine seeking after abstinence. We show that two distinct VP DRD3+ neuronal populations projecting to either the lateral habenula (LHb) or the ventral tegmental area (VTA) display different patterns of activity during drug seeking following abstinence from cocaine self-administration and that selective suppression of elevated activity or DRD3 signaling in the LHb-projecting population reduces drug seeking. Together, our results uncover how circuit-specific DRD3-mediated plasticity contributes to the process of drug relapse. • DRD3-mediated plasticity in the VP drives post-abstinence cocaine-seeking behavior • VP DRD3 signaling regulates dopamine release in the NAc latSh during seeking • VP DRD3+ projections to the LHb and VTA display differing activity during seeking • DRD3 signaling/activity of LHb-projecting VP DRD3+ neurons drives seeking behavior Pribiag et al. show that ventral pallidum dopamine receptor D3 signaling regulates drug seeking following prolonged abstinence from cocaine self-administration via activation of a subpopulation of neurons projecting to the lateral habenula. This regulation feeds back to influence dopamine release in the lateral shell of the nucleus accumbens during drug seeking. [ABSTRACT FROM AUTHOR]