Living longer without simultaneously extending years spent in good health ("health span") is an increasing societal burden, demanding new therapeutic strategies. Hydrogen sulfide (H<sub>2</sub>S) can correct disease-related mitochondrial metabolic deficiencies, and supraphysiological H<sub>2</sub>S concentrations can pro health span. However, the efficacy and mechanisms of mitochondrion-targeted sulfide delivery molecules (mtH<sub>2</sub>S) administered across the adult life course are unknown. Using a <i>Caenorhabditis elegans</i> aging model, we compared untargeted H<sub>2</sub>S (NaGYY4137, 100 &#
xb5;M and 100 nM) and mtH<sub>2</sub>S (AP39, 100 nM) donor effects on life span, neuromuscular health span, and mitochondrial integrity. H<sub>2</sub>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<sub>2</sub>S donor-mediated health span. Developmentally administered mtH<sub>2</sub>S (100 nM) improved life/health span vs. equivalent untargeted H<sub>2</sub>S doses. mtH<sub>2</sub>S preserved aging mitochondrial structure, content (citrate synthase activity) and neuromuscular strength. Knockdown of H<sub>2</sub>S metabolism enzymes and FoxO/<i>
daf-16</i> prevented the positive health span effects of mtH<sub>2</sub>S, whereas DCAF11/<i>
wdr-23</i> - Nrf2/<i>
skn-1</i> oxidative stress protection pathways were dispensable. Health span, but not life span, increased with all adult-onset mtH<sub>2</sub>S treatments. Adult mtH<sub>2</sub>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 <i>
elt-6</i>/<i>
elt-3</i> transcription factor circuit. H<sub>2</sub>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<sub>2</sub>S doses required for health span extension, combined with efficacy in adult animals, suggest mtH<sub>2</sub>S is a potential healthy aging therapeutic.