Introduction Increases in C-reactive protein (CRP) are used to track the inflammatory process of COVID-19 and are associated with disease state progression. Decreases in heart rate variability (HRV) correlate with worsening of disease states. This observational study tracks changes in HRV relative to changes in CRP in COVID-19 patients. Materials and Methods In accordance with an Institutional Review Board-approved study, 17 patients were followed using the wearable, noninvasive Tiger Tech Warfighter Monitor (WFM) that records HRV from a single limb electrocardiogram. Intermittent, daily short-segment data sets of 5 to 7 minutes over a minimum of 7 days were analyzed. Changes in HRV were compared to changes in CRP. Results Decreases in HRV of greater than 40% preceded a 50% increase in CRP during the ensuing 72 hours in 10 of the 12 patients who experienced a dramatic rise in CRP. The effectiveness of HRV as a leading indicator of a rise in CRP was evaluated; the sensitivity, specificity, positive predictive value, and negative predictive value for 40% decreases in HRV preceding 50% increases in CRP were 83.3%, 75%, 90.9%, and 60%, respectively. Conclusion Substantial decreases in HRV preceded elevations in CRP in the ensuing 72 hours with a 90.9% positive predictive value. Early detection of increasing inflammation may prove vital in mitigating the deleterious effects of an abnormal inflammatory response, particularly in COVID-19 patients. This capability could have a major impact in triage and care of moderate to severe COVID-19 patients in major medical centers as well as field hospitals. This study demonstrates the potential value of short-segment, intermittent HRV analysis in COVID-19 patients.