Background and Aims About 20% of patients receiving nucleos(t)ide analogues treatment experienced low‐level viraemia (LLV), which is associated with progression of liver fibrosis and high risk of hepatocellular carcinoma. We aimed to evaluate the effectiveness and safety of switching from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in ETV‐treated patients with LLV. Methods In this prospective study, ETV‐treated patients with LLV, presented to our hospital from December 2018 to October 2019, were enrolled. Switching to TAF or continuing ETV was given. The primary effectiveness endpoint was complete virological response (CVR) at 24 weeks, and the safety endpoint was the first occurrence of any clinical adverse event during the treatment. Results Totally, 211 patients were recruited and propensity score matching (PSM) generated 75 patients in either TAF or ETV group. After PSM, baseline characteristics were balanced in two groups. After 24‐week treatment, the CVR and ALT normalization in TAF group were 62.7% and 47.6%, which were higher than 9.3% and 10.5% in ETV group (OR 16.4, 95% CI 6.6‐40.0, P < .001) respectively. Subgroup analysis showed that switching to TAF achieved favours CVR regardless of the status of sex, age, CHB family history, HBV DNA, HBeAg and cirrhosis, whereas alcohol consumption and diabetes mellitus might compromise the CVR of switching to TAF. Both therapies were well tolerated and had satisfying renal safety. Conclusions For ETV‐treated patients with LLV, switching to TAF is safe enough and superior compared with continuing ETV monotherapy regarding both virological and biochemical benefits.