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Abstract Minimally‐invasive tools to assess tumour presence and burden may improve clinical management. FDG‐PET (metabolic) imaging is the current gold standard for interim response assessment in patients with classical Hodgkin Lymphoma (cHL), but this technique cannot be repeated frequently. Here we show that microRNAs (miRNA) associated with tumour‐secreted extracellular vesicles (EVs) in the circulation of cHL patients may improve response assessment. Small RNA sequencing and qRT‐PCR reveal that the relative abundance of cHL‐expressed miRNAs, miR‐127‐3p, miR‐155‐5p, miR‐21‐5p, miR‐24‐3p and let‐7a‐5p is up to hundred‐fold increased in plasma EVs of cHL patients pre‐treatment when compared to complete metabolic responders (CMR). Notably, in partial responders (PR) or treatment‐refractory cases (n = 10) the EV‐miRNA levels remain elevated. In comparison, tumour specific copy number variations (CNV) were detected in cell‐free DNA of 8 out of 10 newly diagnosed cHL patients but not in patients with PR. Combining EV‐miR‐127‐3p and/or EV‐let‐7a‐5p levels, with serum TARC (a validated protein cHL biomarker), increases the accuracy for predicting PET‐status (n = 129) to an area under the curve of 0.93 (CI: 0.87‐0.99), 93.5% sensitivity, 83.8/85.0% specificity and a negative predictive value of 96%. Thus the level of tumour‐associated miRNAs in plasma EVs is predictive of metabolic tumour activity in cHL patients. Our findings suggest that plasma EV‐miRNA are useful for detection of small residual lesions and may be applied as serial response prediction tool.