Introduction: Cough is a common reflex that serves a protective role, but when persistent, it can severely affect patients’ quality of life. Despite its high prevalence, current treatment options remain limited. Traditional antitussives such as codeine and dextromethorphan present notable side effects, underscoring the need for safer and more effective alternatives. Methods: This study evaluated and compared the antitussive efficacy of classic (codeine, cloperastine, dextromethorphan, levodropropizine) and novel (gefapixant) agents using a citric acid-induced cough model in guinea pigs. Animals were pretreated with the selected compounds, and cough frequency, latency to first cough, and cough intensity were assessed using acoustic recordings and quantitative analysis. Results: Codeine, cloperastine, and gefapixant produced a significant reduction in cough frequency and markedly increased latency to the first cough, with comparable efficacy at the highest doses tested. In contrast, dextromethorphan and levodropropizine did not significantly affect these parameters. Additionally, cloperastine, codeine, and gefapixant reduced cough intensity, while none of the treatments significantly altered cough duration. Conclusions: In this preclinical model, cloperastine and gefapixant demonstrated antitussive effects comparable to codeine but without the known narcotic-associated risks. These findings highlight the potential clinical relevance of both centrally and peripherally acting non-opioid alternatives. Continued investigation of these agents may help address the unmet need for safer and more effective cough treatments.