Background <p>The co-ingestion of supplements has received attention in sports nutrition science due to its potential to enhance anaerobic performance and buffering capacity. Sodium bicarbonate (NaHCO₃), often co-ingested with beta-alanine, creatine, or caffeine, is widely used, but the synergistic effects remain unclear.</p> Objective <p>This systematic review and meta-analysis aimed to evaluate the effects of co-ingestion of NaHCO₃ with beta-alanine, creatine, or caffeine on exercise and physiological parameters, including anaerobic exercise performance, buffering capacity, blood lactate, and perceived fatigue. The aim of the present study was to evaluate the effects of co-ingestion of NaHCO₃ with beta-alanine, creatine, or caffeine compared to NaHCO₃ alone on anaerobic performance, buffering capacity, and rate of perceived exertion (RPE).</p> Methods <p>A systematic search of PubMed, Web of Science, and Scopus was conducted up to January 16, 2025. Randomized controlled trials (RCTs) evaluating acute or chronic co-supplementation involving NaHCO₃ and reporting outcomes such as anaerobic power, buffering capacity, blood pH, or power output were included. Data extraction and risk-of-bias assessment (using the Cochrane RoB 2 tool) were performed independently by two reviewers. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Heterogeneity was assessed via the <i>I</i>² statistic. Sensitivity analyses and publication bias analyses were conducted. Certainty of evidence was analyzed using GRADE.</p> Results <p>A total of 14 randomized controlled trials were included. Analyses by supplement type showed that co-ingestion of sodium bicarbonate with beta-alanine, creatine, or caffeine did not significantly improve mean or peak power compared with NaHCO₃ alone. However, the co-ingestion of NaHCO₃ and creatine was associated with a significant reduction in blood lactate levels (SMD =  − 0.405; 95% CI: − 0.725 to − 0.086; <i>p</i> = 0.013). In the overall pooled analysis across all co-ingestion protocols, no significant differences were observed for mean power (SMD = 0.11; 95% CI: − 0.08 to 0.30; <i>p</i> = 0.255; <i>I</i>² = 0%), peak power (SMD = 0.08; 95% CI: − 0.17 to 0.32; <i>p</i> = 0.535; <i>I</i>² = 0%), blood lactate (SMD = 0.34; 95% CI: − 0.24 to 0.92; <i>p</i> = 0.248; <i>I</i>² = 84.5%), and HCO₃⁻ (SMD =  − 0.16; 95% CI: − 0.57 to 0.25; <i>p</i> = 0.437; <i>I</i>² = 77.3%. Publication bias was assessed using funnel plots and Egger’s test, and sensitivity analyses confirmed the robustness of the findings.</p> Conclusion <p>Co-ingestion of NaHCO₃ with beta-alanine, creatine, or caffeine does not appear to provide additional benefits over single supplementation for improving anaerobic performance or buffering capacity, though specific combinations may influence certain physiological markers such as blood lactate.</p>