The secondary impact of the COVID-19 pandemic affects a world after one year facing adversities in a multiple mourning process due to the sudden and massive loss of human lives, confinement and physical distancing policies, and substantial socioeconomic losses. The fear of being infected, death, or the worsening of health in those already ill and their caregivers can be strong triggers of emotional distress and risk factors for mental health problems. Conversely, self-compassion skills also transcend to relationships promoting compassionate thoughts and behaviors. Compassion, recognizing the other's suffering and in response to discomfort, contributes to alleviate and create thoughts of empathy and affability for those suffering. Both constructs are in feedback in people confronting life-threatening diseases such as Multiple Sclerosis (MS) but depend on many factors. The Teruel Study retrospectively evaluated the impact of strict confinement in the 44 people with MS of a Spanish province and their caregivers on 1) fears and perceptions of lockdown; 2) compassion and self-compassion; 3) factors promoting compassion, solidarity towards tragedy, understanding, empathy, and commitment to alleviate suffering; 4) physical and mental health. Despite patients considered confinement very difficult to handle, more than caregivers, they were less afraid of COVID-19 or worsening of MS. Still, they recognized their health was worse than before confinement. Reclusion and lack of walks were the worse of confinement. Caregivers also referred to lack of leisure and uncertainty-fear. All agree the best was staying with the family, but some found ‘nothing’ positive. Self-compassion of people with MS remained moderate-high. Despite perceiving their physical and emotional health at medium-moderate levels, physical and cognitive fatigue scores were high. Self-compassion correlated with fatigue and explained 19% variance of global health. Self-judgment shared humanity, isolation, and overidentification correlated with cognitive fatigue and explained 16% of global fatigue. Self-kindness and mindfulness correlated with social functioning. The high compassion of the caregivers did not correlate with any health variable nor with fatigue scales. The current times unveil the complexity and frailty of personal and familiar MS scenarios demanding stronger efforts at medical psychology and socio-sanitary levels in the new COVID-19 era.