Isolated compartment syndrome of the hand, although uncommon, can lead to considerable functional deficits if not treated promptly. The most common etiologies are related to trauma, burns, or electric injuries; however, some cases have been reported after intravenous infiltration events, particularly rapid intravenous contrast injection. In this case report, we describe the development of compartment syndrome in the hand of a critically ill patient with COVID-19 pneumonia and sepsis 16 days after doxycycline infiltration injury. She presented with worsening pain, swelling, bullous eruption, and intrinsic minus hand posturing. Emergent surgical release of intrinsic hand compartments and evacuation of a hematoma resolved her symptoms and preserved hand function. Early recognition and surgical intervention of compartment syndrome of the hand after infiltration injury in medically complex patients will reduce morbidity in this patient population.