Living longer without simultaneously extending years spent in good health (“health span”) is an increasing societal burden, demanding new therapeutic strategies. Hydrogen sulfide (H
2
S) can correct disease-related mitochondrial metabolic deficiencies, and supraphysiological H
2
S concentrations can pro health span. However, the efficacy and mechanisms of mitochondrion-targeted sulfide delivery molecules (mtH
2
S) administered across the adult life course are unknown. Using a
Caenorhabditis elegans
aging model, we compared untargeted H
2
S (NaGYY4137, 100 µM and 100 nM) and mtH
2
S (AP39, 100 nM) donor effects on life span, neuromuscular health span, and mitochondrial integrity. H
2
S donors were administered from birth or in young/middle-aged animals (day 0, 2, or 4 postadulthood). RNAi pharmacogenetic interventions and transcriptomics/network analysis explored molecular events governing mtH
2
S donor-mediated health span. Developmentally administered mtH
2
S (100 nM) improved life/health span vs. equivalent untargeted H
2
S doses. mtH
2
S preserved aging mitochondrial structure, content (citrate synthase activity) and neuromuscular strength. Knockdown of H
2
S metabolism enzymes and FoxO/
daf-16
prevented the positive health span effects of mtH
2
S, whereas DCAF11/
wdr-23
– Nrf2/
skn-1
oxidative stress protection pathways were dispensable. Health span, but not life span, increased with all adult-onset mtH
2
S treatments. Adult mtH
2
S treatment also rejuvenated aging transcriptomes by minimizing expression declines of mitochondria and cytoskeletal components, and peroxisome metabolism hub components, under mechanistic control by the
elt-6
/
elt-3
transcription factor circuit. H
2
S health span extension likely acts at the mitochondrial level, the mechanisms of which dissociate from life span across adult vs. developmental treatment timings. The small mtH
2
S doses required for health span extension, combined with efficacy in adult animals, suggest mtH
2
S is a potential healthy aging therapeutic.