We synthesized and analyzed nine unique copper(II) hydrazylpyridine salicylaldehyde and 1,10-phenanthroline complexes, [Cu(L^1a)(phen)] (Cugdupt1), [Cu(L^2a)(phen)]·(CH₃CN) (Cugdupt2), [Cu(L^3a)(phen)] (Cugdupt3), [Cu(L^4a)(phen)]·(CH₃CN) (Cugdupt4), [Cu(L^5a)(phen)] (Cugdupt5), [Cu(L^6a)(phen)] (Cugdupt6), [Cu(L^7a)(phen)] (Cugdupt7) [Cu(L^8a)(phen)] (Cugdupt8) and [Cu(L^9a)(phen)]·0.5(H₂O) (Cugdupt9). We were motivated by the intriguing properties of the coupled ligands of hydrazylpyridine, salicylaldehyde, and 1,10-phenanthroline. The MTT assay demonstrated that Cugdupt1–Cugdupt9 have higher anticancer activity than L¹H₂–L⁹H₂, phen and cisplatin on A549/DDP cancer cells (A549cis). Cugdupt1–Cugdupt9 were superior to cisplatin with IC₅₀ values of 1.6–100.0 fold on A549cis cells (IC_{50(Cugdupt1–Cugdupt9)} = 0.5–30.5 μM, IC_{50(cisplatin)} = 61.5 ± 1.0 μM). However, Cugdupt1–Cugdupt9 had lower cytotoxicity toward the HL-7702 normal cells. Cugdupt1 and Cugdupt8 can induce reduction of mitochondrial respiratory chain complexes I/IV (MRCC-I/IV), mitophagy pathways, and eventually protein regulation and adenosine triphosphate (ATP) depletion in A549cis cells. The findings indicated that Cugdupt1 and Cugdupt8 caused cell death via both ATP diminution and mitophagy pathways. Finally, Cugdupt8 demonstrated high efficacy and no obvious cytotoxicity in A549 tumor-bearing mice. This study thus helps evaluate the potential of the hydrazylpyridine salicylaldehyde–copper(II)–1,10-phenanthroline compounds for cisplatin-resistant tumor therapy.