This study was aimed at developing a synthetic strategy of gradual increase in the steric bulk of ruthenium-based olefin metathesis pre-catalysts for organic solvent nanofiltration (OSN) processes. A series of five enlarged second-generation Hoveyda type pre-catalysts was prepared and characterized. The structural modifications were performed on the benzylidene ligand of an unmodified Hoveyda (II) pre-catalyst. The catalytic activity of the catalysts was evaluated in a model reaction of ring closing metathesis (RCM). All enlarged catalysts showed good stabilities and activities comparable to those of the unmodified Hoveyda II pre-catalyst. Cross-flow nanofiltration of these catalysts exhibited very high retentions (up to 98.5%) confirming the potential of structural modifications coupled with OSN for efficient catalysts separation.