Long-term complications, such as extensive fatigue and cognitive issues, are known from various infections, including SARS-CoV-2, influenza virus, or Borrelia burgdorferi. The pathology is mostly unknown and differs between patients. Unfortunately, there is currently no common and effective treatment. In this perspective, we imply that post-acute infectious syndromes are due to a variety of factors, including among others diminished tissue perfusion, tissue infiltration by viruses, inflammation, and oxidative stress, and that not one specific biomarker can be used to measure these syndromes. Thus, we suggest that a score based on a number of criteria/factors should be used to assess post-acute infectious syndromes. Consequently, probably not one single treatment can be used to treat this group of patients, and we suggest a multimodal treatment regimen comprising a combination of pharmacotherapy, such as metformin and naltrexone with anti-inflammatory effects, alongside physical therapies such as extracorporeal apheresis and transcutaneous neurotherapy. This combined approach aims to reduce biomarker levels and enhance cognitive functions. This implies that a reset of the systems can be achieved by a multimodal approach based on a score for post-acute infectious syndromes.