Although nanozymes have drawn a great attention over the past decade, the activities of peroxidase‐like, oxidase‐like and catalase‐like nanozymes are often pH dependent with elusive mechanism, which largely restricts their application. Therefore, a systematical discussion on the pH related catalytic mechanisms of nanozymes together with the methods to overcome this limitation is in need. In this review, various nanozymes exhibiting pH dependent catalytic activities are collected and the root causes for their pH dependence are comprehensively analyzed. Subsequently, regulatory concepts including catalytic environment reconstruction and direct catalytic activity improvement to break this pH restriction are summarized. Moreover, applications of pH independent nanozymes in sensing, disease therapy and pollutant degradation are overviewed. Finally, current challenges and future opportunities on the development of pH independent nanozymes are suggested. It is anticipated that this review will promote the further design of pH independent nanozymes and broaden their application range with higher efficiency.This article is protected by copyright. All rights reserved