Introduction: Given that susceptibility to the new SARS-CoV-2 virus was universal, even individuals in excellent health, such as professional athletes, were infected, fell ill, isolated and tried to return to their usual physical fitness, training and competitions, as soon as possible which ago. That is why it was necessary to restore a high level of running performances, which required complete recovery, as well as timely detection of complications of the disease. This study aimed to explore the features of COVID-19 among professional football athletes during two seasons of competition with different dominant variants of the SARS-CoV-2 virus, in terms of the dynamics of infection, the clinical presentation of the infection and leading symptoms, the length of physical inactivity and the time to return to full form, describe clusters of infection and to measure the match running performances of the players in both soccer seasons. Participants and methods: Participants were all professional male players of the same soccer club competing in the first Croatian football league during season 1 (2020/2021) and season 2 (2021/2022). During both seasons, all nasopharyngeal and pharyngeal swabs were analyzed using real-time reverse transcriptase polymerase chain reaction (RT-PCR) to identify SARS-CoV-2. In this study data was used regarding dominant virus variants isolated at a national level by genome sequencing. Epidemiological surveying was carried out according to the structured questionnaire for COVID-19 of the World Health Organization. Data were collected on the emergence of infection clustering. Match running performances were measured using a GPS device. Results: The players had significantly more symptoms (p = 0.002), longer periods of physical inactivity (p = 0.006), longer self-assessed periods to reach the full form (p = 0.034), and more frequent symptoms one months after onset in season 1 (2020/2021) (time of Wuhan wild strain and Alpha VOC) than in season 2 (2021/2022) (time of Omicron VOC). No cardiac involvement was noticed. Although the clinical presentation of infection was milder in season 2, the players exhibited significantly more deviations from standard biochemical blood values, though these changes had no clinical significance at the time of the study. Four clusters of infection were observed, the largest in season 2. Omicron variant did not negatively affect player’s performance in contrast to the viruses from season 1 when a difference in accelerations and decelerations of high intensity was observed before and after infection. Conclusion: In professional soccer players, COVID-19 was a mild or asymptomatic disease that did not require hospital care, regardless of the dominant viral variant. The clusters were probably caused by non-compliance with preventive measures. Certain changes to the return-to-play protocol made based on the findings from research in Season 1 on the same sample of players were properly implemented as they helped the athletes to return to their pre-infection running performances relatively quickly in Season 2.