Demographics - ≥18 years of age and above the age of majority as defined for their state at the time of the screening visit. - English fluency adequate for communication and able to self-complete the patient-reported outcomes instruments. - Reside in Connecticut, Florida, and New York Disease Characteristics - Prior SARS-CoV-2 infection is required. Documented confirmation of previous COVID-19 infection from either a documented positive PCR test and/or medical records from a healthcare provider (HCP) that coincides with the diagnosis of long-COVID from a healthcare provider. - Symptoms consistent with long COVID that began within 4 weeks of the index infection and persisted for >12 weeks. These symptoms, according to the World Health Organization definition, 'include fatigue, shortness of breath, cognitive dysfunction but also others, and generally have an impact on everyday functioning. Symptom(s) may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness'. - Baseline "fair" or worse general health status and "good" or better before the index infection and no obvious other reason for the depressed general health status. This is determined from a single-item general health question on the pre-randomization surveys and comorbidity questions. Surveys and Health Records • Have connected health records and completed baseline surveys so assessments can be made before randomization of eligibility for the trial. Documentation in the subject's medical record of a physical examination, including vital signs measurement, by a HCP performed after the onset of post-COVID symptoms or within 3 months prior to randomization, whichever is more recent, is required. Usual Source of Care • Have a usual source of medical care with medical record documentation as required above. (The purpose is to have a health care provider who can be notified of their involvement in the trial and can be a source of care for any adverse effects.) Informed Consent • Willing and able to provide informed consent, complete the surveys, clinical assessments, and biospecimen collections. The study does not have sites and participants will not need to travel for any study visits.

Medical Conditions - HIV infection as determined by laboratory testing at screening. - Acute medical illness currently or within the past 2 weeks, including COVID-19 infection. - Known medical history of active liver disease (other than nonalcoholic hepatic steatosis), including chronic or active hepatitis B or C infection, primary biliary cirrhosis, Child-Pugh Class B or C, or acute liver failure. (ALT or ALT level ≥2.5 X ULN or total bilirubin ≥2 X ULN (≥3 X ULN for Gilbert's syndrome) as determined by laboratory testing at screening. - Receiving dialysis or renal impairment (eGFR estimate <60 mL/min/1.73 m2 ) as determined by laboratory testing at screening. - Any comorbidity requiring hospitalization and/or surgery within 7 days before trial entry, or that is considered life threatening within 30 days before trial entry, as determined by the Yale team. - History of hypersensitivity or other contraindication to any of the components of the trial intervention, as determined by the Yale team. - Other medical or psychiatric condition, in the Yale team's judgment, that makes the participant inappropriate for the trial. - Immunocompromised, as defined by the CDC; "Examples of medical conditions or treatments that may result in moderate to severe immunocompromise include but are not limited to: - Active treatment for solid tumor and hematologic malignancies. - Hematologic malignancies associated with poor responses to COVID-19 vaccines regardless of current treatment status (e.g., chronic lymphocytic leukemia, non-Hodgkin lymphoma, multiple myeloma, acute leukemia). - Receipt of solid-organ transplant or an islet transplant and taking immunosuppressive therapy. - Receipt of chimeric antigen receptor (CAR)-T-cell therapy or hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppressive therapy). - Moderate or severe primary immunodeficiency (e.g., common variable immunodeficiency disease, severe combined immunodeficiency, DiGeorge syndrome, Wiskott-Aldrich syndrome). - Advanced or untreated HIV infection (people with HIV and CD4 cell counts less than 200/mm3, history of an AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV). - Active treatment with high-dose corticosteroids (i.e., 20 ≥ mg of prednisone or equivalent per day when administered for 2 or more weeks), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, tumor necrosis factor blockers, and other biologic agents that are immunosuppressive or immunomodulatory". - Any concomitant prior chronic condition that has caused debilitating symptoms, even if episodic, such as myalgic encephalomyelitis/chronic fatigue syndrome, chronic Lyme disease, multiple sclerosis, fibromyalgia, mast cell activation disorder, and small fiber neuropathy, postural orthostatic tachycardia syndrome, lupus erythematosus, and others or any prior condition associated with immune dysfunction. Prior/Concomitant Therapy - Current or expected use of any medications or substances that are highly dependent on CYP3A4 for clearance, and for which elevated plasma concentrations may be associated with serious and/or life-threatening events during treatment and for 4 days after the last dose of the trial drugs. - Concomitant use of any medications or substances that are strong inducers of CYP3A4 are prohibited within 28 days prior to first dose of nirmatrelvir/ritonavir and during trial treatment. A list of these medications will be provided. - Prior treatment with nirmatrelvir/ritonavir within 2 months prior to randomization. - Prior treatment with nirmatrelvir/ritonavir at any time if for more than 5 days. - Individuals who plan to get a COVID-19 vaccine between the time of consent through Day 28 will be excluded from the trial. Prior/Concurrent Clinical Trial Experience - Unwillingness to abstain from participating in another interventional clinical study with an investigational compound or device, including those for long COVID therapeutics, through 90 days. (People may be concurrently enrolled in observational studies in general; including the Yale LISTEN study.) - Previous administration with any investigational drug in a clinical study within 30 days or 5 half-lives preceding the first dose of trial intervention used in this trial (whichever is longer). Diagnostic Assessments Known history of any of the following abnormalities within the past 6 months or currently present: - AST or ALT level ≥2.5 X ULN. - Total bilirubin ≥2 X ULN (≥3 X ULN for Gilbert's syndrome). - eGFR <60 mL/min/1.73 m2 within 6 months of the screening visit, using the updated CKD-EPI formula without the race term. - Absolute neutrophil count <1000/mm3. Other Exclusions - Potential participants who are or plan to become pregnant or breastfeeding. Female potential participants will have a pregnancy test during screening. - Anyone directly involved in the conduct of the trial and their immediate family members.