The relationship between hyperhomocysteinemia (HHcy) and obesity with low skeletal muscle mass (LMM) has not been established. We aim to assess the association between HHcy and the coexistence of obesity and LMM in asymptomatic adult population. We conducted a population-based cross-sectional study among asymptomatic individuals who underwent measurements of plasma homocysteine and body composition analysis. HHcy was defined as > 15 umol/L, obesity as body mass index ≥ 25 (kg/m2), and LMM as skeletal muscle index less than 2 SD below the sex-specific mean of young adults. The participants were classified into ‘control’, ‘obesity alone’, ‘LMM alone’, and ‘obesity with LMM’. Among 113,805 participants, the prevalence of HHcy was 8.3% in control, 8.7% in obesity alone, 10.0% in LMM alone, and 13.0% in obesity with LMM (p for trend < 0.001). In a multivariable logistic regression analysis, the associations showed a positive trend for HHcy along the groups from obesity alone, to LMM alone, and to obesity with LMM. HHcy was independently associated with the presence of LMM alone (adjusted odds ratio 1.186 [95% confidence interval 1.117–1.259]) and obesity with LMM (1.424 [1.134–1.788]), respectively. This study demonstrated that HHcys was more strongly associated with coexistence of obesity and LMM than either condition alone in the adult population.