Background and objective: The safety of individual low- and no-calorie sweeteners (LNCS) has been well established over decades, yet interest has grown in potential combined effects from concurrent exposure. This study evaluated (a) whether existing cumulative risk assessment (CRA) frameworks are appropriate for LNCS and (b) their applicability to aspartame, saccharin, sucralose, acesulfame-K, steviol glycosides, and cyclamate. Methods: Regulatory CRA guidance and safety evaluations for each LNCS were reviewed. Toxicological data from repeat-dose and reproductive/developmental studies were synthesized by organ system and effect thresholds. A structured review of human microbiome studies was also conducted. Evidence was assessed for shared structure, target organ toxicity, and mode of action relevant to CRA frameworks. Results: Existing frameworks rely on grouping chemicals with shared structure or mode of action; however, LNCS lack common structural features, toxicological profiles, and target organ effects. Kidney findings observed at high doses were inconsistent, species-specific, and considered toxicologically insignificant. Microbiome effects were variable, sweetener-specific, and not indicative of cumulative impact. Conclusions: LNCS do not exhibit properties necessary for cumulative assessment under established CRA methods. Evidence supports no cumulative effects at typical intake levels, reinforcing the adequacy of individual acceptable daily intakes (ADIs) for safety evaluation.