COVID-19 mitigation measures such as lockdown and social distancing could have a negative impact on mental health. Understanding their impact is essential to minimize adverse effects on individuals, families, and communities. This longitudinal study aimed to evaluate the emotional impact of the COVID-19 pandemic and social isolation in the Argentinian population over time. An online survey evaluating anxiety and depression symptoms, positive affect, and negative affect, was completed by 3,833 people at three different time points: immediately after the lockdown began, 12–15 days after the first assessment, and after 47–51 days. Various socio-demographic factors were considered. A series of mixed repeated-measures ANOVAs were performed, with results showing significant increases over time (with small effect sizes) in anxiety, depression, negative affect, and a decrease in positive affect. Some socio-demographic factors such as age, gender, number of children, and educational level differentially affected these changes. These results suggest that mental health and quality of life were negatively affected, making it essential to monitor emotional distress and other mental health problems in the population and encourage the implementation of support and containment devices to cope with these adverse effects.