The prospective association of muscular weakness with the risk of all-cause and premature mortality in a general population remains unknown. The aim of this study was to investigate the prospective effects of handgrip strength and muscular weakness on risk for all-cause and premature mortality over 10 years using a large nationwide sample of Korean adults. The study participants included 9229 middle and older adults (4131 males and 5098 females), using data from the Korean Longitudinal Study of Ageing 2006–2016. Muscular strength was measured using handgrip strength. Muscle weakness was defined using the sex-specific handgrip strength index based on the Asian Working Group on Sarcopenia in Older People (AWGSOP). The primary outcome was all-cause and premature mortality assessed based on the death certificate. The hazard ratio (HR) for all-cause mortality was negatively associated with level of handgrip strength independent of potential confounding factors (HR: 2.06, 95% confidence interval [CI]: 1.62–2.63 for lowest quartile vs. highest quartile). When examined using muscle weakness defined using the AWGSOP diagnosis, the mortality was 1.56 times higher in the weak group (HR: 1.56, 95% CI: 1.36–1.78). We also found that risk of premature mortality was observed in the lowest quartile (HR: 2.34, 95% CI: 1.80–3.05) and the muscle weakness group (HR: 1.80, 95% CI: 1.52–2.13) in the fully adjusted model. Our 10-year prospective cohort study showed that handgrip strength and muscle weakness are strongly associated with an increased risk of all-cause and premature mortality in healthy middle-aged and older adults.