In this study, we have designed an electrochemical biosensor based on topological material BiSe for the sensitive detection of SARS-CoV-2 in the COVID-19 pandemic. Flake-shaped BiSe was obtained directly from high-quality single crystals using mechanical exfoliation, and the single-stranded DNA was immobilized onto it. Under optimal conditions, the peak current of the differential pulse voltammetry method exhibited a linear relationship with the logarithm of the concentration of target-complementary-stranded DNA, ranging from 1.0 × 10 to 1.0 × 10 M, with a detection limit of 3.46 × 10 M. The topological material BiSe, with Dirac surface states, enhanced the signal-to-interference plus noise ratio of the electrochemical measurements, thereby improving the sensitivity of the sensor. Furthermore, the electrochemical sensor demonstrated excellent specificity in recognizing RNA. It can detect complementary RNA by amplifying and transcribing the initial DNA template, with an initial DNA template concentration ranging from 1.0 × 10 to 1.0 × 10 M. Furthermore, the sensor also effectively distinguished negative and positive results by detecting splitting-synthetic SARS-CoV-2 pseudovirus with a concentration of 1 copy/μL input. Our work underscores the immense potential of the electrochemical sensing platform based on the topological material BiSe in the detection of pathogens during the rapid spread of acute infectious diseases.