Relativistic mixed-reference spin-flip (MRSF)-TDDFT is developed considering the spin–orbit coupling (SOC) within the mean-field approximation. The resulting SOC-MRSF faithfully reproduces the experiments with very high accuracy, which is also consistent with the values by four-component (4c) relativistic CASSCF and 4c-CASPT2 in the spin–orbit-energy splitting calculations of the C, Si, and Ge atoms. Even for the fifth-row element Sn, the SOC-MRSF yielded accurate splittings (∼ 3 % error). In the SOC calculations of the molecular 4-thiothymine with a third-row element, SOC-MRSF values are in excellent agreement with those of the SO-GMC-QDPT2 level, regardless of geometries and exchange-correlation functionals. The same SOC-MRSF predicted the anticipated chance of S1 (nπ*) → T1 (ππ*) intersystem crossing, even in thymine with only second-row elements. With its accuracy and practicality, thus, SOC-MRSF is a promising electronic structure protocol in challenging situations such as nonadiabatic molecular dynamics (NAMD) incorporating both internal conversions and intersystem crossings in large systems.