Background and Objective: One of the challenging issues over the ages has been spiritual and mental dilemmas leading to numerous miseries and mortifications in human societies. From the perspective of Islam, one of the maladies of human in addition to physical maladies is spiritual one affecting human beings with a kind of suspect and anxiety which is manifested in terms of suspicion and fragile faith in God and leads to display of manners well-matched with ungodly and wicked habits which, in turn, induces acts of unbelievers. In contrast, Quran considers a healthy person as one who does not go astray and who has spiritually achieved piety of soul and spirit. The Holy Quran entitles a person of healthy soul (Salim o-nnafs) if he is not a slave of inordinate desires. To meet this goal, the present research embarked on evaluation of Shia Muslims interpretations of malady of soul focusing on Tafsir- al Mizan (Allameh Tabatabaii) with specific reliance on the commentaries and perspectives of deceased Allameh Hosseini Tehrani. Materials and Methods: To fulfill the objectives of this study this descriptive/ analytical and library based research was applied. Results: A striking issue from the perspective of Tafsir-al Mizan is the similarity of soul disease with physical diseases which tend to aggravate by time and if not treated, it will diverge into a chronic disease and will subsequently end in death. It is worth mentioning that aggravation of heart disease stems from negligence of a patient concerning the detrimental activities worsening severity of disease of the heart (exactly similar to physical diseases). Conclusion: In Quranic perspective, if an individual suffers from heart disease and if he desires to be treated for his illness, this needs to repent of his sins towards Glorified God. Quran mentions that one of the distinct futures of repentance is faith in God, proper and virtuous behavior and thoughts. Furthermore, in the same perspective, those who suffer from soul disease are not scared of acquiring worldly assets at the price of being deprived of religion and also such people assign a high priority to mortal worldly positions over piousness.