As global transportation, space exploration, and energy consumption demand grows, safer and more efficient turbine engines, rocket engines, and power generators are needed. To meet the rapidly growing demand for transportation and energy consumption worldwide, more efficient engines and generators necessitate higher operating temperatures which in turn requires alloys with retained strength levels at ever increasing temperatures. In the past decade, refractory complex concentrated alloys (RCCAs) have gained prominence through numerous reports of superior strengths at higher homologous temperatures than conventional refractory and super alloys. However, these RCCAs, comprised of transition metals from subgroups IV, V, and VI, tend to be brittle at room temperature, hindering their broad applicability. Recent findings reveal that interstitial impurities may significantly contribute to, and convolute observations of, the ductility and strength of RCCAs at room temperature. The studies presented in this dissertation investigate the role of interstitial impurities such as O and N in RCCAs and provide an understanding and insight into their role in the design and processing of RCCAs. In the first investigation, a literature review examines and discusses the field’s current understanding of the role of interstitial impurities, in the microstructure and mechanical behavior of RCCAs. Moreover, context is provided from the binary interactions of interstitial impurities with refractory metals and their contribution to developing and processing conventional refractory alloys as a framework to gain insight into interstitial impurity mechanisms in RCCAs. With the understanding of interstitial impurity interactions with RCCA constituents, more holistic approaches to the design of RCCAs are suggested to engineer the mechanisms of intended and unintended interstitial impurities through alloy design and processing. The second investigation quantified the origins of interstitial impurities from the feedstocks and residual gases during plasma arc melting (PAM) in the MoNbTaW RCCA. In the PAM synthesized MoNbTaW RCCAs, the thermodynamic drive for grain boundary segregation and oxide formation was characterized using atom probe tomography (APT) and analyzed using density functional theory (DFT) calculations. With this understanding, alloy design and processing techniques necessary to control interstitial impurities in RCCAs were then described. In the third study, the role of O in the NbTaTiHf RCCA, a previously developed RCCA with room temperature ductility, was investigated. The role of O in the microstructural evolution of the NbTaTiHf alloy and the alloy’s sensitivity to O were analyzed and an additional design criterion for future RCCA design was provided. In the fourth and fifth studies, advanced mechanical properties, specifically tensile creep and fracture toughness, of the NbTaTiHf RCCA were investigated, providing further insight to the design and processing of ductile RCCAs. Together, these studies represent systematic and meticulous approaches to investigate how interstitial impurities can influence the design and processing of RCCAs. From this insight, criteria and techniques for designing and processing RCCAs with high strength and ductility could be recommended.