Abstract: High-precision quantitative analysis of trace elements constitutes a pivotal research focus in materials science, environmental monitoring, and nuclear science. Conventional external calibration or internal standardization methods are widely used, yet their measurement accuracy is frequently compromised by instrumental signal instability and matrix effects. Meanwhile, the application of high-confidence isotope dilution mass spectrometry (IDMS) is fundamentally constrained by the requirement for elements with multiple stable isotopes and the limited availability of enriched isotopic spikes. To circumvent these limitations, this study established and validated a universal “pseudo-isotope dilution mass spectrometry” (Pseudo-IDMS) strategy designed to achieve high precision quantification for mono-isotopic elements (e.g., ⁴⁵Sc, ⁸⁹Y, ¹⁶⁹Tm, ¹⁹⁷Au) and nuclides lacking suitable spike systems (e.g., ²³⁷Np). Unlike traditional IDMS, Pseudo-IDMS utilizes an element with similar chemical properties and mass-to-charge ratio as a “pseudo” spike, transforming quantification of target nuclide into a precise measurement of the isotope ratio between the target and the diluent element. By systematically characterizing cross-element mass fractionation behavior using inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) and multi-collector inductively coupled plasma tandem mass spectrometry (MC-ICP-MS), this study established reliable correction models to evaluate mass fractionation across different element pairs. The method was rigorously tested across various scenarios using typical systems, including Sc-Ti/V, Y-Sr, Tm-Ho/Er/Yb, and Au-Pt for stable elements, and the ²³⁷Np-U/Pu system for actinides. The results demonstrated that for ICP-MS/MS analysis, measurement precisions (2σ) for Sc, Y, Tm and Au were better than 1.20%, 0.35%, 0.30% and 0.40%, respectively. These results represented a significant improvement over the 3%-7% precision typically associated with conventional external calibration standard methods. Furthermore, leveraging MC-ICP-MS allowed for more flexible cross-element fractionation correction using mass-adjacent isotopic reference materials. This configuration achieved a detection limit of 10⁻¹⁶ g/g for ultra-trace ²³⁷Np and a precision of 1.82% (2σ) for samples at the 10⁻¹³ g/g level. The practical utility of the method was successfully demonstrated through the accurate quantification of ²³⁷Np in soil samples from Xinjiang. This work overcomes the intrinsic dependency of IDMS on enriched isotopes by successfully resolving the challenge of cross-element mass fractionation correction. By eliminating the need for calibration curves, Pseudo-IDMS avoids uncertainties introduced by curve fitting and ensures direct traceability of results. This methodology is distinguished by three key advantages that underscore its value: first, it offers expanded applicability, breaking the IDMS barrier to enable high precision analysis of mono-isotopic elements; second, it realizes “zero-Standard” quantification via MC-ICP-MS, utilizing mass-adjacent isotopic reference materials to correct fractionation for radionuclides lacking concentration standards; third, it ensures process robustness, as the chemically similar pseudo spike undergoes synchronous transformation with the target analyte during pretreatment, making the final isotopic ratio reflective of initial content regardless of yield losses. While Pseudo-IDMS significantly enhances analytical accuracy and versatility, it introduces certain complexities. According to uncertainty propagation principles, the introduction of a cross-element proxy adds new sources of uncertainty and requires selection of the reference element, thereby increasing the complexity of experimental design. However, this sacrifice in theoretical simplicity is outweighed by the method’s substantial gain in universality and its effective suppression of major uncertainty sources. Ultimately, Pseudo-IDMS offers a high throughput (approx. 10 min/sample) and high precision technical foundation, presenting broad application prospects in nuclide monitoring, advanced materials development, and biological tracing.