The continuous evolution of SARS-CoV-2 and its variants poses persistent challenges to global public health. As a sublineage of the XDV.1 variant, NB.1.8.1 has rapidly emerged as a dominant strain worldwide, triggering a new wave of infections. Representing a product of viral adaptation, this variant has acquired several critical amino acid mutations—including A435S and T478I—which enhance its transmissibility and immune evasion capabilities compared to the ancestral XDV.1 lineage. This review systematically summarizes the genomic characteristics, epidemiological features, and immune escape potential of NB.1.8.1. It emphasizes that sustained genomic surveillance and serological assessments are crucial for informing public health response strategies, guiding vaccine development, and optimizing containment measures.