Depression is more prevalent in obese individuals and those with diabetes, compared to the general population. This study examined the effect of resistance training on depressed mood in individuals with high (HiMF, n ≥ 2) and low (LoMF, n ≤ 1) numbers of risk factors for metabolic syndrome and type 2 diabetes. The primary hypothesis was that resistance training would significantly reduce depressed mood, as measured by the Cardiac Depression Scale (CDS), in individuals with HiMF. Fifty-five middle-aged volunteers (50.8 ± 0.9 years, mean ± SEM) from the general community participated in the study. After initial allocation to HiMF or LoMF, participants were randomly allocated to 4 groups, HiMF training (HiMFT), HiMF control (HiMFC), LoMF training (LoMFT), and LoMF control (LoMFC). Participants underwent resistance training involving major muscle groups on 3 d·wk(-1) for 10 weeks. Before and after interventions (training or control), participants completed the CDS to assess change in the level of depressed mood. Following resistance training, the CDS score of the HiMFT group was reduced by -14.8 ± 4.9 points on the CDS, a significant improvement in comparison to both baseline (p = 0.01) and HiMFC (p = 0.049) values. No significant change was observed for LoMFT. In the HiMF group only, the percent change in relative muscle strength was correlated with the Δ change in CDS; r = -0.46, p = 0.008. Resistance exercise training programs that consist 7 exercises for the major muscle groups at both low-moderate and moderate-high intensities appear to alleviate depressed mood in individuals with clusters of metabolic risk factors.