Background:　Deficient　sleep　is　implicated　in　nicotine　dependence　as　well　as　depressive　and　anxiety　disorders.　The　hypothalamus　regulates　the　sleep-wake　cycle　and　supports　motivated　behavior,　and　hypothalamic　dysfunction　may　underpin　comorbid　nicotine　dependence,　depression　and　anxiety.　We　aimed　to　investigate　whether　and　how　the　resting　state　functional　connectivities　(rsFCs)　of　the　hypothalamus　relate　to　cigarette　smoking,　deficient　sleep,　depression　and　anxiety.　Methods:　We　used　the　data　of　64　smokers　and　198　age-　and　sex-matched　adults　who　never　smoked,　curated　from　the　Human　Connectome　Project.　Deficient　sleep　and　psychiatric　problems　were　each　assessed　with　Pittsburgh　Sleep　Quality　Index　(PSQI)　and　Achenbach　Adult　Self-Report.　We　processed　the　imaging　data　with　published　routines　and　evaluated　the　results　at　a　corrected　threshold,　all　with　age,　sex,　and　the　severity　of　alcohol　use　as　covariates.　Results:　Smokers　vs.　never　smokers　showed　poorer　sleep　quality　and　greater　severity　of　depression　and　anxiety.　In　smokers　only,　the　total　PSQI　score,　indicating　more　sleep　deficits,　was　positively　associated　with　hypothalamic　rsFCs　with　the　right　inferior　frontal/insula/superior　temporal　and　postcentral　(rPoCG)　gyri.　Stronger　hypothalamus-rPoCG　rsFCs　were　also　associated　with　greater　severity　of　depression　and　anxiety　in　smokers　but　not　never　smokers.　Additionally,　in　smokers,　the　PSQI　score　completely　mediated　the　relationships　of　hypothalamus-rPoCG　rsFCs　with　depression　and　anxiety　severity.　Conclusions:　These　findings　associate　hypothalamic　circuit　dysfunction　to　sleep　deficiency　and　severity　of　depression　and　anxiety　symptoms　in　adults　who　smoke.　Future　studies　may　investigate　the　roles　of　the　hypothalamic　circuit　in　motivated　behaviors　to　better　characterize　the　inter-related　neural　markers　of　smoking,　deficient　sleep,　depression　and　anxiety.　©　2024　The　Authors