Abstract Purpose Multimorbidity leads to decreasing health-related quality of life (HRQoL). Telemedicine may help to improve HRQoL. The present study was conducted to show (I) differences in HRQoL and changes in HRQoL over time in elderly, multimorbid individuals with and without depression and/or mild cognitive impairment (MCI) using a telemonitoring application (TMA) and (II) associations between engagement with measurements by study participants using a TMA and changes in their HRQoL. Methods The present feasibility study was part of a longitudinal intervention study. Recruited general practitioners (GPs) enrolled individuals and assigned them to risk groups according to absence/presence of depression and/or MCI. Depression was assessed using the Geriatric Depression Scale (GDS-15), MCI using the Mini-Mental State Examination (MMSE), and HRQoL using the SF-12. The TMA consisted of tablets, software, and measuring devices. Measured vital data were transferred to a care and case manager for monitoring and possible intervention. Results Nine GPs recruited 177 individuals, 97 of whom were included in the HRQoL analysis. Significantly lower physical and mental component summary (PCS/MCS) scores were revealed in study participants with depression, and with both depression and MCI, compared to participants with no mental disorders. PCS scores did not differ between study dates, but MCS scores had significantly increased over time. Participants’ engagement with measurements was significantly associated with an increased MCS score, but not with the PCS score. Discussion Depression and/or MCI are negatively associated with the HRQoL of elderly, multimorbid people using a TMA. Engagement of individuals with vital data measurements via a TMA may increase their mental HRQoL. Mentally impaired people should be closely involved as co-designers and experts in development processes of TMAs to benefit from tailored solutions. An individual’s increased mental HRQoL can be a decisive factor in their engagement with a GP treatment regimen and telemonitoring processes.