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Slow wave sleep (SWS) is essential for supporting cognitive functioning. Understanding its influence could guide interventions to enhance mental performance and mitigate cognitive deficits associated with insufficient sleep. This systematic review investigated the impact of pharmacological interventions on SWS and cognitive performance in healthy volunteers and clinical populations. A comprehensive literature search identified 1286 references, of which 27 articles (representing 27 studies) met the inclusion criteria. Only RCTs that reported on both SWS and cognition were eligible for inclusion. Pharmacological interventions targeted mainly the GABAergic, serotonergic, histaminergic, noradrenergic, and hypocretinergic systems. The included studies varied considerably in type of pharmacological agent used, sleep condition, control condition, and the specific cognitive assessments employed to measure targeted neurocognitive domains. Most investigated agents effectively increased SWS duration; however, this rarely translated into cognitive improvement. These findings suggest that cognitive benefits are not driven by SWS duration alone, underscoring the need to integrate additional sleep metrics. Future research should consider moving beyond a singular focus on SWS duration and incorporate quality measures of slow wave activity. In addition, the current clinical test conditions should preferably be replaced by ecologically valid study conditions and cognitive metrics to increase generalizability and representativeness.