The COVID-19 pandemic represents a health crisis with a high amount of loneliness, which in turn may be associated with negative mental health outcome like psychological distress. This chapter aimed to investigate if meaning in life mediated the effect of loneliness on symptoms of psychological distress. A young adult sample (N = 605, 75.7% women) completed the measures of loneliness, psychological distress, and meaning in life. The results indicated that meaning in life mediated the relations between loneliness and psychological distress symptoms. This relation was significant at low, medium, and high levels of meaning in life. The study shows that experience of loneliness is associated with symptoms of psychological distress. Level of meaning in life differentiates the direct and indirect effect of loneliness on psychological distress. Knowledge about the effect of loneliness in response to a health crisis is important for developing treatment and prevention strategies for loneliness, psychological distress, and meaning in life.