γ-Valerolactone (GVL) is readily obtained by the hydrogenation of levulinic acid (LA) and is considered a sustainable platform chemical for the production of bio-based chemicals. Herein the performance and stability of Ru-based catalysts (1 wt.% Ru) supported on TiO2 (P25) and ZrO2 (monoclinic) for LA hydrogenation to GVL was investigated in the liquid phase in batch and continuous-flow reactors using water and dioxane as solvents. Particular attention is paid to the influence of both process-derived and biogenic impurities on LA hydrogenation performance. Benchmark continuous-flow experiments at extended times on stream (i.e., 190 h, 10 wt.% LA, 50 bar H2, 150 oC in dioxane, 90 oC in water, WSHV of 2.4 gfeed gcat·h-1 in dioxane, 3.6 gfeed gcat·h-1 in water) showed that the deactivation profiles are distinctly different for both solvents. In dioxane, the Ru/ZrO2 catalyst is clearly more stable than Ru/TiO2, whereas the latter is slightly more stable in water. Detailed characterization of spent catalysts after long-term stability runs showed that deactivation of Ru/TiO2 is strongly linked to reduction of the TiO2 support and a reduction of the specific surface area. Ru/ZrO2 showed no signs of support reduction and displayed morphological and structural stability, although some deposition of carbonaceous material was observed. Impurities in the LA feed such as HCOOH, H2SO4, furfural (FFR), 5-hydroxymethylfurfural (HMF), humins, and sulfur-containing amino acids impacted catalyst performance differently. Results reveal rapid, yet reversible loss of activity for both catalysts upon HCOOH addition to LA, attributed to its preferential adsorption on Ru sites and possible CO poisoning. A more gradual drop in activity was found when co-feeding HMF, FFR, and humins for both solvents. The presence of H2SO4, cysteine, and methionine all resulted in irreversible deactivation of the Ru catalysts. The results obtained provide new insights into the (ir)reversible (in)sensitivity of Ru-based hydrogenation catalysts to potential impurities in LA feeds, knowledge essential for next-generation catalyst development.