In early 2020, Greece was affected by the SARS-CoV-2 epidemic, and since then, the continuous emergence of fast-spreading variants has caused surges of new SARS-CoV-2 infections. In this study, we performed genomic, phylogenetic, and epidemiological analyses to investigate the SARS-CoV-2 epidemic in northwestern Greece. From March 2020 to February 2022, nasopharyngeal samples obtained from patients suspected to have COVID-19 were tested for SARS-CoV-2 detection. Complete SARS-CoV-2 genomic sequences were generated from selected positive samples. Northwestern Greece experienced four distinct waves of the epidemic following the first wave, which was mainly observed in Attica and other parts of Greece. The positivity index was rising throughout the pandemic waves in several geographical units, with the highest levels recorded in prominent tourist destinations characterized by high agricultural density. The phylogenetic analyses revealed 34 different lineages, with B.1, B.1.1, B.1.1.305, B.1.1.318, B.1.177, B.1.1.7, B.1.617.2, AY.43, and BA.1 being the most prevalent lineages in the region. Although multiple lineages were co-circulating, each pandemic wave was dominated by a different lineage. The SARS-CoV-2 epidemic in northwestern Greece was characterized by the successive introduction of new lineages, resulting in surges of new SARS-CoV-2 infections.