Stage I: - Body mass index (BMI) less than or equal to (<=) 35 kilogram per meter square (kg/m^2) - Positive laboratory test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or respiratory infection with recent exposure to a person with laboratory-proven SARS-CoV-2 - Patient has an ordinal scale score between 5 and 7, inclusive, using the WHO 7OS - Hypoxemia defined by saturation of peripheral oxygen (SpO2) of less than (<) 95 percent (%) on room air or Acute respiratory distress syndrome (ARDS) - Occurrence of at least two of the following criteria: fever greater than (>) 38.0 degree celsius, tachycardia >90 beats/minute, tachypnea >20 breaths/minute, leucocytosis >12*109 per liter (/L) or leucopoenia <4 *10^9/L - Enrollment must occur within 72 hours from the initiation of mechanical ventilation or high-flow oxygen - A signed informed consent form (ICF) from the patient or the patient's legally authorized representative must be available (telephone consent is acceptable) - Female patients may not be pregnant, lactating, or breastfeeding - Female patients of childbearing potential must have negative result for pregnancy test at screening - Male patients must agree to use a barrier method of contraception during the study and for 90 days after the last dose - Participants must have an estimated glomerular filtration rate of greater than or equal to (>=) 45 milliliter per minute per 1.73 meter square (mL/min/1.73 m^2) at screening - Must agree not to enroll in another study of an investigational agent prior to completion of this study. Stage II: - Positive laboratory test for SARS-CoV-2 or respiratory infection with recent exposure to a person with laboratory-proven SARS-CoV-2 - Patient has an ordinal scale score between 5 and 8, inclusive, using the WHO 10OS. - Patients with an ordinal score of 5 must be receiving oxygen by mask at a rate of 10 L or greater - Hypoxemia defined by SpO2 of <95% on room air or diagnosed with ARDS - Hyperinflammation (elevated CRP > upper limit of local normal for laboratory range) at screening - A signed ICF from the patient or the patient's legally authorized representative must be available (telephone consent is acceptable) - Female patients may not be pregnant, lactating, or breastfeeding - Female patients of childbearing potential must have negative result for pregnancy test at screening - Patients must have an estimated glomerular filtration rate of >= 30 mL/min/1.73 m^2 at screening - Male patients must agree to use a barrier method of contraception during the study and for 90 days after the last dose - Must agree not to enroll in another study of an investigational agent prior to completion of this study.

Stage I: - Not expected to survive for more than 24 hours - Underlying clinical condition where, in the opinion of the investigator, it would be extremely unlikely that the patient would come off ventilation (eg, motor neuron disease, Duchenne muscular dystrophy, or rapidly progressive interstitial pulmonary fibrosis) - Severe chronic obstructive pulmonary disease requiring long-term home oxygen therapy or mechanical ventilation (noninvasive ventilation or via tracheotomy) except for continuous positive airway pressure or bi-level positive airway pressure used solely for sleep-disordered breathing - Congestive heart failure, defined as New York Heart Association Class IV - Acute left ventricular failure or myocardial infarction - Currently receiving extracorporeal membrane oxygenation (ECMO) therapy - Receiving renal dialysis therapy for chronic renal failure - Moderate to severe liver failure (Childs-Pugh Score >12) - Presence of any active malignancy (other than nonmelanoma skin cancer) that required treatment within the last 2 years - Lung transplant patient - WHO Class III or IV pulmonary hypertension - Documented deep venous thrombosis or pulmonary embolism within past 3 months - Major trauma in the preceding 5 days - Concurrent treatment with immune modulatory study drugs (e.g., anti-IL6 antibodies, Janus kinase (JAK) kinase inhibitors) or other agents with actual or possible direct acting antiviral activity against SARS-CoV-2 within 30 days or 5 half-lives, whichever is longer, prior to dosing with OP-101; except for those that have received FDA emergency-use authorization and have become standard of care (SOC). Concurrent treatment with corticosteroids is permitted if participant has documented continued hypoxemia (SpO2 of <95% on room air) and hyper-inflammation (CRP>=10 mg/L) at screening. - Has lost or donated >450 mL of whole blood or blood products within 30 days before screening - Has any finding that, in the view of the investigator or medical monitor, would compromise the patient's safety requirements - Is employed by the Sponsor, the contract research organization, or the study site (permanent, temporary contract worker, or designee responsible for the conduct of the study), or is a family member (spouse, parent, sibling, or child) of the Sponsor, contract research organization, or study site employee. Stage II: - Not expected to survive for more than 24 hours - Underlying clinical condition where, in the opinion of the investigator, it would be extremely unlikely that the patient would come off ventilation (e.g., motor neuron disease, Duchenne muscular dystrophy, or rapidly progressive interstitial pulmonary fibrosis) - Severe chronic obstructive pulmonary disease requiring long-term home oxygen therapy or mechanical ventilation (noninvasive ventilation or via tracheotomy) except for continuous positive airway pressure or bi-level positive airway pressure used solely for sleep-disordered breathing - Congestive heart failure, defined as New York Heart Association Class IV - Acute left ventricular failure or myocardial infarction - Currently receiving ECMO therapy - Receiving renal dialysis therapy for end stage renal disease - Moderate to severe liver failure (Childs-Pugh Score >12) - Presence of any active malignancy (other than nonmelanoma skin cancer) that required treatment within the last 2 years - Lung transplant patient - WHO Class III or IV pulmonary hypertension - Documented deep venous thrombosis or pulmonary embolism within past 3 months - Major trauma in the preceding 5 days - Concurrent treatment with approved or emergency use authorized immune modulatory study drugs (eg, anti-IL6 antibodies [tocilizumab], JAK kinase inhibitors [baricitinib]) or other investigational agents with actual or possible direct acting antiviral activity against SARS-CoV-2 within 30 days or 5 half-lives, whichever is longer, before dosing with OP-101. - Has lost or donated >450 mL of whole blood or blood products within 30 days before screening - Mechanical ventilation for >72 hours at the time of dosing - Has any finding that, in the view of the investigator or medical monitor, would compromise the patient's safety requirements - Is employed by the Sponsor, the contract research organization, or the study site (permanent, temporary contract worker, or designee responsible for the conduct of the study), or is a family member (spouse, parent, sibling, or child) of the Sponsor, contract research organization, or study site employee.