Intravenous thrombolysis leads to a reduction of post-stroke disability. No data exist about whether depression and poor quality of life (QoL) remain relevant problems in patients with good functional outcome. We assessed mood and QoL at 3 and 6 months after stroke in consecutive patients who received intravenous thrombolysis in stroke centers and telemedicine hospitals within the TEMPiS network. The Beck Depression Inventory (BDI) was used with BDI ≥18 indicating clinically relevant depressive symptoms. Stroke specific quality of life (SSQOL) was used for QoL assessment with the definition of SSQOL total score <60% for poor QoL. Associations of BDI and SSQOL with baseline parameters and modified Rankin scale (mRS) in follow-up were analyzed. In patients with known mRS 0-4 at 3 months (N = 213), BDI was available in 74% and SSQOL in 77%. At 3 and 6 months, 23 and 18% of patients had clinically relevant depressive symptoms; 25 and 24% reported a poor QoL. The mRS at 3 months correlated with BDI (r = 0.43, p < 0.01) and SSQOL (r = -0.75, p < 0.01). BDI ≥18 was observed in 11% of patients with mRS 0-1 and 16% in mRS 0-2. Severe stroke (NIHSS ≥12) at admission (OR 1.23, 0.57-2.66; p = 0.57) was not predictive for depressive symptoms but for poor QoL (OR 2.77, 95%CI 1.34-5.74). Depressive symptoms and impaired QoL are observed in a substantial proportion of stroke patients at 3 months after intravenous thrombolysis. Health professionals should be aware that thrombolysed patients may have relevant mood disorders despite good functional outcome.