Environmental contamination from antineoplastic drugs poses a significant occupational health risk to healthcare professionals. Herein, we evaluated the efficacy of a recently developed decontamination method using hypochlorous acid (HClO) water and alkaline electrolyzed water (AEW) compared to conventional cleaning, focusing on the physicochemical properties of target drugs. Decontamination efficacy was assessed on work desks and clean benches using an ATP bioluminescence assay (RLU values). Additionally, a wipe test was conducted on stainless-steel plates contaminated with 5-fluorouracil (5-FU), gemcitabine (GEM), and paclitaxel (PTX) to quantify residual drug concentrations after cleaning with either distilled water/ethanol or HClO/AEW. Cleaning with HClO and AEW significantly reduced the RLU values compared to those from conventional cleaning (distilled water and ethanol) (p < 0.05), achieving levels below the standard threshold of 200 RLU. Regarding the wipe test, HClO and AEW demonstrated superior removal efficacy for the hydrophilic drugs 5-FU and GEM (p < 0.05). Conversely, residual levels of the highly lipophilic drug PTX (log P = 2.5) were significantly higher following HClO/AEW cleaning than those from the ethanol-based method. The combination of HClO and AEW provides excellent baseline cleanliness and is highly effective for decontaminating surfaces with hydrophilic antineoplastic drugs. However, its efficacy in removing lipophilic agents, such as PTX which may form hydrophobic films, is limited. These findings suggest that a multilayered decontamination strategy, such as HClO treatment with an ethanol wipe, is essential for comprehensive safety, and provide a scientific basis for selecting cleaning protocols based on the log P-values of handled hazardous drugs.