<p>Loneliness has been identified as an important global issue potentially linked with poor mental health and suicide, which requires novel research to illuminate its underlying protective factors. This national study of adults in Japan aimed to address this knowledge gap by examining mattering—the feeling of being valued and experiencing personal significance to others—as a protective factor from loneliness, poor mental health outcomes, and suicidality. A cross-sectional national panel survey using a survey vendor was conducted in 2024 with 1010 Japanese adults (486 women and 524 men) sampled in population-representative distributions from Japan’s eight geographic regions. Logistic regression was performed to identify key predictors of loneliness, including mattering, and linear regressions examined the influence of loneliness and mattering on depression, anxiety, alcohol use, and suicidality. Regressions indicated that (1) having a higher sense of mattering predicted a lower likelihood of experiencing loneliness, and (2) loneliness and sense of mattering predicted depression, anxiety, and suicidality. These findings suggest mattering may be a novel target for the prevention of loneliness, depression, anxiety, and suicidality in Japan.</p>