The current study focused primarily on the associations that feelings of not mattering have with life satisfaction, stress, and distress among students trying to cope with the uncertain and novel circumstances brought about by the COVID-19 pandemic. A sample of 350 University students from Italy completed measures that included the General Mattering Scale and the Anti-Mattering Scale, as well as measures of self-esteem, difficulties in emotion regulation, life satisfaction, perceived stress, anxiety, and depression. Psychometric analyses confirmed the factor structure, reliability, and validity of the General Mattering Scale and the Anti-Mattering Scale. As expected, feelings of not mattering were associated with lower life satisfaction as well as with greater reported difficulties in emotion regulation, stress, and distress. Mattering and self-esteem were both unique predictors of levels of life satisfaction during the pandemic. The results of mediational analyses suggested that individuals who feel as though they do not matter may be especially vulnerable to stress, depression, and anxiety and this may promote a decline in life satisfaction. Given the potential destructiveness of feelings of not mattering, in general but especially during a global pandemic, it is essential to proactively develop interventions and programs that are designed to enhance feelings of mattering and reduce anti-mattering experiences and feelings.