Six half-sandwich Ir(III) complexes were prepared, thoroughly characterized and screened for their in vitro cytotoxicity at the A2780 and A2780R human cancer cells. The best-performing complex 6 was studied against some other cell lines where it showed different cytotoxic profile from cisplatin. Complex 6 also exhibited relevant selectivity towards the cancer cells over the non-cancerous ones. Complex 6 was markedly more accumulated by the A2780 cells than cisplatin and induced different cell cycle changes than cisplatin. Additionally, complex 6 was for the first time among half-sandwich iridium(III) complexes also assessed at spheroid (3D) cancer cells, where its potency remained significantly better than for cisplatin.