Reactions of hexaniobate with vanadate in the presence of Ni2+, Zn2+, or Cu2+ have furnished three high‐nuclear vanadium cluster‐substituted heteropolyoxoniobates (HPNs): {Ni(en)3}5H{VVNb8VIV8O44}⋅9 H2O (1), (H2en)Na2[{Zn(en)2(Hen)}{Zn(en)2(H2O)}2{PNb8VIV8O44}]⋅11 H2O (2), and Na{Cu(en)2}3{[Cu(en)2]2[PNb8VIV8O44]}⋅11 H2O (3) (en=1,2‐diaminoethane). Their structures have been determined and characterized by single‐crystal X‐ray diffraction analysis, thermogravimetric analysis (TGA), and elemental analysis. Structural analysis has revealed that compounds 1–3 contain similar {V8}‐substituted [XVNb8VIV8O44]11− (X=P, V) clusters, obtained by inserting a {V8} ring into tetravacant HPN [XNb8O36]27−. To the best of our knowledge, compounds 1–3 represent the first high‐nuclear vanadium cluster‐substituted HPNs, and compound 1 is the largest vanadoniobate cluster yet obtained in HPN chemistry. Nickel and zinc cations have been introduced into HPNs for the first time, which might promise a more diverse set of structures in this family. Antitumor studies have indicated that compounds 1 and 2 exhibit high activity against human gastric cancer SGC‐7901 cells, SC‐1680 cells, and MG‐63 cells.