Background: Although there have been no reported cardiac arrests in space to date, the risk of severe medical events occurring during long-duration spaceflights is a major concern. These critical events can endanger both the crew as well as the mission and include cardiac arrest, which would require cardiopulmonary resuscitation (CPR). Thus far, five methods to perform CPR in microgravity have been proposed. However, each method seems insufficient to some extent and not applicable at all locations in a spacecraft. The aim of the present study is to describe and gather data for two new CPR methods in microgravity. Materials and Methods: A randomized, controlled trial (RCT) compared two new methods for CPR in a free-floating underwater setting. Paramedics performed chest compressions on a manikin (Ambu Man, Ambu, Germany) using two new methods for a free-floating position in a parallel-group design. The first method (Schmitz–Hinkelbein method) is similar to conventional CPR on earth, with the patient in a supine position lying on the operator’s knees for stabilization. The second method (Cologne method) is similar to the first, but chest compressions are conducted with one elbow while the other hand stabilizes the head. The main outcome parameters included the total number of chest compressions (n) during 1 min of CPR (compression rate), the rate of correct chest compressions (%), and no-flow time (s). The study was registered on clinicaltrials.gov (NCT04354883). Results: Fifteen volunteers (age 31.0 ± 8.8 years, height 180.3 ± 7.5 cm, and weight 84.1 ± 13.2 kg) participated in this study. Compared to the Cologne method, the Schmitz–Hinkelbein method showed superiority in compression rates (100.5 ± 14.4 compressions/min), correct compression depth (65 ± 23%), and overall high rates of correct thoracic release after compression (66% high, 20% moderate, and 13% low). The Cologne method showed correct depth rates (28 ± 27%) but was associated with a lower mean compression rate (73.9 ± 25.5/min) and with lower rates of correct thoracic release (20% high, 7% moderate, and 73% low). Conclusions: Both methods are feasible without any equipment and could enable immediate CPR during cardiac arrest in microgravity, even in a single-helper scenario. The Schmitz–Hinkelbein method appears superior and could allow the delivery of high-quality CPR immediately after cardiac arrest with sufficient quality.