PURPOSE: To identify which acute and 6-month domain-specific cognitive impairments impact mood, participation, and stroke-related quality of life 6 months post-stroke. MATERIALS AND METHODS: A prospective cohort of 430 stroke survivors completed the Oxford Cognitive Screen (OCS) acutely and 6 months post-stroke. Participants completed the Stroke Impact Scale (SIS) and Hospital Depression and Anxiety Scale (HADS) at 6 months. Multivariable regression analyses assessed whether severity of, and domain-specific, cognitive impairment acutely and at 6 months was associated with composite 6-month SIS scores, each SIS subscale, and HADS scores. RESULTS: Increased severity of acute and 6-month cognitive impairment was associated with lower 6-month SIS composite scores independent of age, sex, education years, and stroke severity (both p < 0.001). Domain-specific impairments in memory (p < 0.001) and attention (p = 0.002) acutely, and language (p < 0.001), memory (p = 0.001) and number processing (p = 0.006) at 6 months showed the strongest associations with worse SIS composite scores. Severity of acute and 6-month cognitive impairment was associated with poorer functioning in each SIS subscale, and greater levels of depression (acute p = 0.021, 6-months p < 0.001), but not anxiety (p = 0.174, p = 0.129). CONCLUSIONS: Both acute and 6-month domain-specific cognitive impairments, particularly in memory, were found to negatively impact overall functional and mood outcomes 6 months post-stroke.