Background <p>Oral nutritional supplements (ONS) are commonly prescribed to provide protein and energy to hemodialysis (HD) patients. There is a debate about the appropriate timing to administer ONS. We aimed to study the effect of different timings of ONS on variable outcomes in HD patients.</p> Methods <p>This research is a prospective, randomized, multicentric clinical trial (RCT) that included 120 patients on regular HD. Patients were allocated to receive ONS (25 gm protein powder/HD session) for 8&#xa0;weeks either predialytic (1&#xa0;h before the start of the session), intradialytic (2&#xa0;h after the start of the session), or interdialytic (on non-dialysis days). Laboratory parameters, blood pressure (BP), dialysis adequacy, and nutritional parameters were assessed during the study.</p> Results <p>At study end, BP at the end of HD dropped significantly in the intradialytic group compared to the other groups (p &lt; 0.001). Serum albumin improved significantly in the predialytic (p &lt; 0.001) and intradialytic (p = 0.039) groups. The mean subjective global assessment score increased significantly in the interdialytic group (p = 0.040). The Kt/V and urea reduction ratio decreased significantly only in the intradialytic group (<i>p</i> value &lt; 0.001 and 0.001). Serum sodium, potassium, phosphorus, cholesterol, triglycerides, and adverse events did not significantly differ between the different groups.</p> Conclusions <p>Predialytic ONS supplementation is a favorable option due to improved serum albumin with minimal effects on hemodynamics and dialysis adequacy compared to intradialytic and interdialytic supplementation.</p> Clinical Trials registration <p>ClinicalTrials.gov NCT05953636.</p> <p>First registration date: 1/07/2023.</p>