This study aimed to examine the associations of handgrip strength (HGS) and asymmetry with health-related quality of life among South Korean older adults. We enrolled 7395 older adults from the Korea National Health and Nutrition Examination Survey. Health-related quality of life was measured using the EuroQol-5 Dimension. Weakness was defined as a HGS of <26 kg for men and <18 kg for women. Handgrip strength symmetry was defined as an HGS ratio of 0.9:1.1, and HGS asymmetry was defined as a ratio outside that range. Data were analyzed using the Rao-Scott χ2, F test, and multivariate logistic regression. Compared with those in the “symmetric HGS and not weak” group, those in the “asymmetric HGS and weak” group had impaired health-related quality of life for all variables among men (odds ratios [ORs] = 1.67-3.75, 95% confidence interval [CI] [1.14, 6.27]). A greater risk of impaired self-care (SC; odds ratio [OR] = 2.33, 95% CI [1.67, 3.25]) and anxiety/depression (AD; OR = 1.40, 95% CI [1.04, 1.88]) was observed among women in the “asymmetric HGS and weak” group. Handgrip weakness and asymmetry are associated with impaired health-related quality of life. Handgrip asymmetry can be a clinical marker of health-related quality of life in older adults and must be measured alongside HGS.