Over the past decade, science has experienced a growing rise in nanotechnology with ground-breaking contributions. Through various laborious technologies, nanomaterials with different architectures from 0 D to 3 D have been synthesized. However, the 3 D flower-like organic-inorganic hybrid nanomaterial with the most direct one-pot green synthesis method has attracted widespread attention and instantly become research hotspot since its first allusion in 2012. Mild synthesis procedure, high surface-to-volume ratio, enhanced enzymatic activity and stability are the main factor for its rapid development. However, its lower mechanical strength, difficulties in recovery from the reaction system, lower loading capacity, poor reusability and accessibility of enzymes are fatal, which hinders its wide application in industry. This review first discusses the selection of non-enzymatic biomolecules for the synthesis of hybrid nanoflowers followed by the innovative advancements made in organic-inorganic hybrid nanoflowers to overcome aforementioned issues and to enhance their extensive downstream applications in transduction technologies. Besides, the role of hybrid nanoflower has been successfully utilized in many fields including, water remediation, biocatalyst, pollutant adsorption and decolourization, nanoreactor, biosensing, cellular uptake and others, accompanied with several quantification technologies, such as ELISA, electrochemical, surface plasmon resonance (SPR), colorimetric, and fluorescence were comprehensively reviewed. © 2021 Taylor & Francis Group, LLC.