Background 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. Methods 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 weeks either predialytic (1 h before the start of the session), intradialytic (2 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. Results At study end, BP at the end of HD dropped significantly in the intradialytic group compared to the other groups (p < 0.001). Serum albumin improved significantly in the predialytic (p < 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 (p value < 0.001 and 0.001). Serum sodium, potassium, phosphorus, cholesterol, triglycerides, and adverse events did not significantly differ between the different groups. Conclusions 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. Clinical Trials registration ClinicalTrials.gov NCT05953636.