In the literature, very few ytterbium(III) complexes have been reported to display promising anti-cancer activities without photoactivation or conjugation to cytotoxic counterparts/radionuclides. By employing porphyrinato ligands, which provide a rigid molecular scaffold for the ytterbium(III) ion and enhance cellular-uptake efficacy, we have prepared and structurally characterized a series of ytterbium(III) porphyrin complexes showing potent anti-cancer activities with cytotoxic IC₅₀ values down to the sub-micromolar range. The notable example is an ytterbium(III) octaethylporphyrin complex (1) which exists as a dimeric hydroxyl-bridged complex [Yb₂(OEP)₂(μ-OH)₂] (where H₂OEP = octaethylporphyrin) in CH₂Cl₂ solution and in solid state, and as monomeric [Yb(OEP)(DMSO)(OH)(OH₂)] in DMSO/aqueous solution. Unlike various anti-cancer lanthanide complexes which are proposed to target cellular DNA, transcriptomics data, bioinformatics connectivity map analysis and biochemical experiments altogether indicate that 1 exerts its anti-cancer effect through apoptosis that is highly associated with the endoplasmic reticulum stress pathway.