A novel creatine blend (creatine nitrate mixed with creatinine, CN-CRN) has been anecdotally suggested to be superior to traditional creatine formulations for bioavailability and performance. However, does CN-CRN supremely affects creatine levels in the blood and skeletal muscle of healthy humans remain currently unknown. This randomized, controlled, double-blind, crossover trial evaluated the acute effects of single-dose CN-CRN on serum creatine levels, and 5-days intervention with CN-CRN on skeletal muscle creatine and safety biomarkers in healthy men. Ten healthy young men (23.6 ± 2.9 years) were allocated to receive either CN-CRN (3 grams of creatine nitrate mixed with 3 grams of creatinine), pure creatine nitrate (3 grams, CN), or regular creatine monohydrate (3 grams, CRM) by oral administration. We found that CN-CRN resulted in a more powerful rise in serum creatine levels comparing to either CN or CRM after a single-dose intervention, as evaluated with the area under the concentration–time curve calculation (701.1 ± 62.1 (µmol/L) × min versus 622.7 ± 62.9 (µmol/L) × min versus 466.3 ± 47.9 (µmol/L) × min; p <.001). The peak serum creatine levels at 60-min sampling interval were significantly higher in CN-CRN group (183.7 ± 15.5 µmol/L), as compared to CN group (163.8 ± 12.9 µmol/L) and CRM group (118.6 ± 12.9 µmol/L) (p <.001). This was accompanied by a significantly superior increase in muscle creatine levels after CN-CRN administration at 5-days follow-up, as compared to CN and CRM, respectively (9.6% versus 8.0% versus 2.1%; p =.01). While 2 out of 10 participants were found to be nonresponsive to CN intervention (20.0%) (e.g., no amplification in muscle creatine levels found at 5-days follow-up), and 3 participants out of 10 were nonresponsive in CRM trial (30%), no nonresponders were found after CN-CRN administration, with individual upswing in total muscle creatine varied in this group from 2.0% (lowest increment) to 16.8% (highest increment). Supplemental CN-CRN significantly decreased estimated glomerular filtration rate (eGFR) at 5-days follow-up, as compared to other interventions (p =.004), with the average reduction was 14.8 ± 7.7% (95% confidence interval; from 9.3 to 20.3). Nevertheless, no single participant experienced a clinically relevant reduction in eGFR (< 60 ml/min/1.73 m2) throughout the course of the trial. Liver enzymes remained in reference ranges throughout the study, with no participant experienced high liver blood tests (e.g., AST > 40 units per L or ALT >56 units per L). Besides, no participant reported any major side effects during the trial, while the odors of CN-CRN and CN formulations were considered somewhat unpleasant in 8 out of 10 participants (80.0%). Our results suggest that CN-CRN is a preferred and relatively safe alternative to traditional creatine formulations for improved creatine bioavailability in the blood and skeletal muscle after single-dose and 5-days interventions.