Background: Carers of people with Alzheimer’s disease often have a high degree of commitment and dedication which may also compromise physical and emotional, leisure, and occupational self-care. This study aimed to explore health-related quality of life (HRQoL) and psychoemotional variables in caregivers with and without caregiver overload and its relationship. Methods: A single-measure cross-sectional correlational study was carried out involving 59 informal caregivers of people with Alzheimer’s disease with a mean age of 59.30 (±10.58). The participants completed the adult HRQoL questionnaires (EQ-5D-3L), Zarit Burden Inventory test, General Happiness Questionnaire, Satisfaction with Life Scale, Rosenberg self-esteem scale, Occupational Balance Questionnaire (OBQ-E), International Fitness Scale (IFIS), Family Apgar scale, and Duke-UNC-11 Functional Social Support Questionnaire. Results: A significantly higher level of HRQoL (p = 0.029) in subjective happiness (p = 0.018), perceived social support (p = 0.046), avoidance (p = 0.034), occupational balance (p = 0.002), life satisfaction (p = 0.037), and self-perceived physical fitness (p = 0.021) was found in caregivers without perceived overload. Also, HRQoL was directly associated with self-perceived physical fitness (β = 0.534; p < 0.001) and occupational balance (β = 0.375; p < 0.001) and self-esteem (β = 0.249; p < 0.016). Conclusions: Caregivers who do not perceive overload have better levels of HRQoL and psychoemotional variables, establishing a relationship between HRQoL with self-perceived physical fitness, occupational balance, and self-esteem.