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Background Adults who are critically ill frequently require multiple intravenous infusions through limited vascular access, making Y-site co-infusion unavoidable. However, much of the primary compatibility literature uses concentrations, diluents and visual-only methods that do not reflect contemporary intensive care unit (ICU) practice, risking false reassurance at the bedside.Objective To create an ICU-specific, concentration-matched Y-site compatibility chart aligned to standardised infusion concentrations and to identify compatible, conditional, incompatible and no-data drug-pairs.Methods We performed a PRISMA (preferred reporting items for systematic reviews and meta-analyses) guided, method-stratified synthesis (1970–2025) of in-vitro Y-site evidence from PubMed, Trissel’s and Micromedex. Classifications privileged instrumented endpoints (pH, turbidimetry, sub-visible particles, high-performance liquid chromatography) over visual inspection. Drug–drug pairs were mapped to our tertiary adult ICU formulary; medicines with an established ward standard were deemed ICU standardised. Outcomes: compatible (C), compatible in saline only (Csf), conditional (concentration/diluent dependent; applied only when at least one medicine was ICU standardised), incompatible—physical (Ie/Ip/It) or chemical (Iq)—or no data (ND).Results Among 4465 mapped drug-pairs, 43.94% were compatible (C 42.37%, Csf 1.57%); 2.53% were conditional; 8.24% were incompatible—predominantly physical; and 45.29% lacked eligible evidence. High-risk clusters included lipid emulsions (eg, propofol, clevidipine), extreme-pH agents (eg, amiodarone, furosemide), phenytoin and calcium salts. For morphine hydrochloride, evidence was sparse (76% ND, 21% compatible, 1% conditional, 2% incompatible). Amiodarone exemplified concentration non-concordance; with an ICU concentration of 15 mg/mL, 34% of amiodarone drug-pairs had compatibility that was concentration dependent.Conclusions At standardised ICU concentrations, fewer than half of potential Y-site pairings are unequivocally compatible and nearly half have no concentration-matched data. A conservative, method-stratified framework anchored to exact concentration and diluent mitigates risk and exposes evidence gaps. Applying a conservative, method-stratified framework anchored to exact concentration and diluent mitigates risk while revealing priority evidence gaps—especially for lipid emulsions, calcium-containing solutions, extreme-pH drugs and opioids. Embedding the chart within the electronic prescribing and medicines administration (EPMA) system can deliver checks, standardise line allocation, reduce uncertain Y-site mixing and prioritise dedicated lumens for high-risk agents.