<p>Younger female adults are more vulnerable to depression than older females, potentially due to a greater affective response to inflammation. This randomized, double-blind, placebo-controlled study evaluated depressed mood and reward responsivity in response to an acute inflammatory challenge in younger as compared to older females. Low-dose endotoxin (0.8 ng/kg of body weight) or placebo was administered to younger (n = 40; age 25–44) and older (n = 53; age 60–80) healthy female adults. Participants provided blood samples and self-reported depressed mood pre-infusion and hourly over 9 h. The Effort Expenditure for Rewards Task (EEfRT) and Probabilistic Reward Task (PRT) assessed reward motivation, sensitivity, and learning at baseline and 2.5 h after infusion. Results showed that age moderated the effect of endotoxin on depressed mood (<i>p</i> = 0.0005), with endotoxin increasing depressed mood in younger (<i>p</i> &lt;0.0001) but not older (<i>p</i> = 0.99) females. Age also moderated the effect of endotoxin on EEfRT reward sensitivity (<i>p</i> = 0.01), with a decrease in reward sensitivity in younger (<i>p</i> = 0.004) but not older (<i>p</i> = 0.43) females, with a similar trend observed for EEfRT reward motivation (<i>p</i> = 0.09). Age did not moderate the effect of endotoxin on PRT reward learning (<i>p</i> = 0.51); endotoxin decreased PRT reward learning in both groups (<i>p</i> = 0.04). Results indicate that younger females have heightened sensitivity to the effects of inflammation, resulting in greater increases in depressed mood and larger deficits in reward responsivity compared to older females. Interventions that target inflammation could be relatively more beneficial in the treatment of depression in younger females, as compared to those who are older. Trial Registration: ClinicalTrials.gov: NCT03256760; NCT03848715.</p>