Fatigue and physical exhaustion are the dominant symptoms of post-coronavirus (COVID-19) conditions that might even develop after only mild acute disease. Post-acute infection syndromes have been observed after various infections, e.g., *Coxiella burnetii*, Ebola, Dengue, Polio, severe acute respiratory syndrome (SARS), Chikungunya, West Nile Virus, *Borrelia*, or *Giardina lamblia*. The similarities in symptoms and courses suggest a high likelihood of common pathogenetic pathways, including persistent infection, autoimmune reactions, dysregulation of the microbiome, inability to repair tissue damage, or endothelial dysfunction. Some herbal drugs, so-called adaptogens, exert effects resulting in an increase in the resistance or regulatory potential of organisms against biological, chemical and physical burden or stress. Therefore, it seems possible that adaptogens can be helpful in cases of post-COVID-19 symptoms. One of these adaptogens is *Rhodiola rosea* L. The proprietary ethanolic extract made from roots and rhizomes of *Rhodiola rosea* WS^®^ 1375 has been reported to modulate neuroinflammation in response to stress stimuli in preclinical models. Moreover, it activated the synthesis or resynthesis of adenosine triphosphate (ATP) in skeletal muscle mitochondria and counteracted muscle fatigue. In three clinical trials with subjects suffering from burnout symptoms, prolonged or chronic fatigue symptoms or life-stress symptoms, clinically relevant improvements of fatigue and exhaustion were reported over 4 to 12 weeks of treatment at a very favorable tolerability and safety profile in heterogeneous patient populations. In conclusion, *Rhodiola rosea* extract WS^®^ 1375 has a promising pharmacological and therapeutic profile for the treatment of fatigue and physical exhaustion associated with post-COVID-19 conditions.