Background: Nursing practice has to contribute to evidence pointing out why there is a need for more nurse-designed randomized control trials (RCTs) focusing on evidence-based practice (EBP). How far this EBP has progressed in different health aspects is usually established by systematic reviews of RCTs. Nurse-led RCTs exist but no study has addressed the essentials of nursing care. Aim: The aim was therefore to determine the essentials of nurses’ interventions by means of nurse-led RCTs in somatic care focusing on the stated context, goals, content, strategies as well as the nurse’s role related to effectiveness. Methods: A systematic review was realized according to Cochrane review assumptions to identify, appraise and synthesize all empirical evidence meeting pre-specified eligibility criteria. The PRISMA statement guided the data extraction process (n = 55) from PubMed and CINAHL. Results: Of the RCTs in somatic care, 71% showed a positive effectiveness of nurse-led interventions, of which the nurse had a significant role with regard to being the main responsible in 67% of the studies. Also, 47% of the RCTs presented a theoretical standpoint related to the nurse-led interventions and most prominent were international evidence-based guidelines. Goals were found to have either a patient-centered or a professional-centered ambition. Strategies were based on patient-directed initiatives, nurse-patient-directed initiatives or nurse-directed initiatives, while contents were built upon either a patient-nurse interaction or a nursing management plan. Conclusions: This review underlines the necessity of a holistic view of a person, as nurse-led RCTs comprising a patient-centered ambition, patient-directed initiative and patient-nurse interaction plan showed beneficial nursing care effectiveness, particularly if theory-based. In a nurse-led RCT, a basic theoretical perspective is advantageous as well as to elucidate the role of the nurse in relation to the estimated effects.