Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. A physically active lifestyle can improve the health-related quality of life (HRQoL) of people with CVD. Nevertheless, adherence to a physically active lifestyle is poor. This study examined the longitudinal (pre-event, 6-, 12-, 24-, and 36-month follow-ups) physical activity profiles in 275 patients (mean age = 57.1 years; SD = 7.87; 84% men) after the first acute coronary event. Moreover, it investigated the associations among physical activity, sense of coherence (SOC), and HRQoL. Physical activity profiles were identified through latent class growth analysis, and linear regressions were then performed to explore the association between physical activity, SOC, and HRQoL. After the cardiovascular event, 62% of patients reached adequate physical activity levels and maintained them over time (virtuous profile). The remaining 38% could not implement (23%) or maintain (15%) a healthy behavior. A strong SOC at baseline (standardized β = 0.19, p = 0.002) predicted the probability of belonging to the virtuous profile. Moreover, a strong SOC at baseline (standardized β = 0.27, p < 0.001), together with the probability of belonging to the virtuous profile (standardized β = 0.16, p = 0.031), predicted a better HRQoL at the final follow-up. Findings showed a strong relationship between SOC, the ability to adopt a physically active lifestyle stably over time, and HRQoL in patients with CVD. They suggest the importance of tailoring physical activity interventions by promoting resilience resources such as SOC to improve patients’ quality of life after an acute coronary event.