Recently, the MoSi2N4(MoN)4n homologous compounds have been synthesized, extending the MA2Z4 family materials to the superthick MA2Z4(MZ)n form. Herein, a first‐principles study on the double‐transition‐metal W2TiSi2N6 and related group VI–IV M2M′Si2N6 nanosheets is performed. Robust structural stability is affirmed in this W2TiSi2N6 nanosheet from the energetic, mechanical, dynamical, and thermal perspectives. Unlike the WSi2N4 and WSi2N4(WN)n systems, the W2TiSi2N6 nanosheet exhibits a semimetal behavior with the top valence and bottom conduction bands touching each other at the Fermi level. With the inclusion of spin–orbit coupling, a nontrivial band gap is opened in the W2TiSi2N6 nanosheet, which has a sizeable bulk gap of 0.11 eV. The Z2 invariant is 1 and a pair of topologically protected edge states emerges in the gap region, confirming that W2TiSi2N6 nanosheet is a quantum spin Hall (QSH) insulator. Through in‐plane strain engineering, the bulk gap can be further increased to 0.23 eV, which is sufficiently large for the room‐temperature QSH effect. Such a large‐gap QSH state is also present in other group VI–IV M2M′Si2N6 systems with the combinations of MM′ = WZr, MoZr, and MoHf. This study demonstrates that the double‐metal M2M′Si2N6 nanosheets are promising candidates to realize fascinating topological quantum states.