The COVID-19 pandemic has had a heavy impact on daily life, leading to physical and psychosocial consequences. Nowadays, clinicians and health researchers are particularly interested in describing and facing the long-term effects of COVID-19, also known as “long-COVID syndrome”. Pandemic fatigue has been defined as a cluster of demotivation, tiredness, and psychological effects that emerge gradually over time after the infection or through the adoption of the recommended measures to combat it. In this study, we report the findings of a large survey conducted in South America involving 1448 participants (mean age: 33.9 ± 11.2 years old) from Argentina, Bolivia, Uruguay, Peru, and Paraguay. An online survey was launched through the common social media based on a specific assessment aimed to detect the prevalence of pandemic fatigue and associated factors. Socio-demographic characteristics, medical, and personal information were collected; the Pandemic Fatigue Scale (PFS) and the Coronavirus Anxiety Scale (CAS) were also administered. We found mid-levels of pandemic fatigue among respondents (21.7 ± 7.95 score at PFS) as well as significant anxiety related to the COVID-19 pandemic (1.56 ± 2.76 score at CAS). In addition, pandemic fatigue was significantly associated with the experience of the loss of a relative/friend due to COVID-19, anxiety related to the infection, and reliance on social media as a primary source of information on the pandemic. Vaccination significantly reduced the levels of fatigue among respondents. Our findings may add to the international debate regarding the long-term health consequences of the COVID-19 pandemic and strategies to manage them in the general population of South America.