We report the breastc ancer stem cell (CSC) potency of two nickel(II)-3,4,7,8-tetramethyl-1,10-phenanthroline complexes, 1 and 3,containingthe non-steroidalanti-inflammatoryd rugs (NSAIDs), naproxen and indomethacin, respectively.T he nickel(II) complexes, 1 and 3 kill breast CSCs and bulk breast cancer cells in the micromolar range. Notably, 1 and 3 display comparable or better potency towards breast CSCs than salinomycin,a ne stablished CSC-activea gent.T he complexes, 1 and 3 also display significantly lower toxicity towardsn on-cancerous epithelial breast cells than breast CSCs or bulk breast cancerc ells (up to 4.6-fold). Mechanistic studiess uggest that 1 and 3 downregulate cyclooxygenase-2(COX-2) in breast CSCs and kill breast CSCs in aC OX-2 dependentm anner.F urthermore, the potencyo f1 and 3 towardsb reast CSCs decreasedu pon co-treatment with necroptosisi nhibitors (necrostatin-1 and dabrafenib), implying that 1 and 3 inducen ecroptosis, an ordered form of necrosis, in breast CSCs. As apoptosis resistance is ah allmark of CSCs, compounds like 1 and 3,w hich potentially provide accesst oa lternative (non-apoptotic) cell death pathways could hold the key to overcoming hard-to-killC SCs. To the best of our knowledge, 1 and 3 are the first compounds to be associated to COX-2 inhibition and necroptosis induction in CSCs.