The aim of this research was to assess the impact of comprehensive medication management (CMM) services on patients’ health-related quality of life (HRQoL) and frequency of adverse drug reactions (ADRs) in older patients with cardiovascular diseases (CVDs). A prospective, pre- and post-intervention study with a one-year follow-up was conducted at the Health Care Centre Zagreb—Centre (HCZC). The Euro-Quality of Life Questionnaire 5 Dimensions 5 Levels (EQ-5D-5L) was used to measure the HRQoL at baseline (initial visit at the HCZC) and 12 months following CMM services. The ADRs collected at the initial assessment of the CMM services and throughout follow-up consultations were analyzed according to the occurrence mechanism, seriousness, expectedness and distribution of the Preferred Term according to the System Organ Class. Following the CMM intervention, 65 patients reported significant improvement in dimensions “self-care” (p = 0.011) and “usual activities” (p = 0.003), whereas no significant change was found in the “mobility” (p = 0.203), “pain/discomfort” (p = 0.173) and “anxiety/depression” (p = 0.083) dimensions and the self-rated VAS scale (p = 0.781). A total of 596 suspected ADR reports were found, the majority at patients’ initial assessment (67.3%), with a mean ± SD of 9.2 ± 16.9 per patient. The CMM services significantly reduced the rate of suspected ADRs, namely 2.7 ± 1.7 ADRs per patient at the initial assessment vs. 1.0 ± 1.5 ADRs per patient at the last consultation (p < 0.001). The obtained results indicate that CMM services may improve patients’ HRQoL. Additionally, as CMM services diminished the proportion of ADRs following 1-year patient follow-up, they may serve as a viable solution for safety management.