Although Owen provided many practical exhortations to aid Christians in the mortification of sin, he believed that “the principal efficient cause of the performance of this duty is the Spirit.” Owen warned against those who attempt to employ “other remedies” towards the mortification of sin. The greatest part of popish religion, Owen wrote, “consists in mistaken ways and means of mortification…vows, orders, fastings, penances, are all built on this ground; they are all for mortifying sin.” The ways and means employed by the Papists are the “doctrines and commandments of men;” God never ordained any of them for the mortification of sin. True mortification is only accomplished by the means that God has appointed. The “self-vexations” of men not sufficient for such a duty. "That none of these ways are sufficient is evident from the nature of the work itself that is to be done; it is a work that requires so many concurrent actings in it as no self-endeavor can reach unto, and is of that kind that an almighty energy is necessary for its accomplishment…" The Spirit, therefore, is the only appointed means by which true mortification is achieved, all other ways are not only vain, but also render a person helpless.
As stated, Owen viewed Romans 8:13 as foundational for the work of mortification. There is a causal connection between the conditional particle and the agent through whom the duty is to be performed. “If by the Spirit you put to death the deeds of the body, you will live.” The principle efficient cause by which mortification is effectuated in the life of the believer is “by the Spirit.” The condition cannot be met unless a person has the Spirit; the Spirit is the single appointed means for mortification in the life of the believer. It is the ministration of the Spirit who functions as the certainty of the coherence and connection between true mortification and eternal life. As stated, mortification is a gift that flows from the cross of Christ. But it is through the work of the Spirit that the gift of mortification and all other gifts are communicated to the believer. Owen wrote, “All communications of supplies and relief, in the beginnings, increasings, actings of grace whatever, from him, are by the Spirit, by whom he alone works in and upon believers.” Romans 8:9 is an important text for Owen to demonstrate that mortification is a gift that is communicated only to the believer, “If we have not the Spirit of Christ, we are none of his.” A man may easier see without eyes, speak without a tongue, than truly mortify one sin without the Spirit.” Sin cannot be killed if a man has no interest in Christ and is without the Spirit.
Owen views the work of the Spirit as the promise and fulfillment of the new covenant. The Spirit is the long awaited promise who, through the life, death, and exaltation of Christ, has been given to do the work of mortification in the life of the believer. Owen refers to Ezek. 36:16, “I will give my Spirit, and take away the stony heart.” The removal of the stony heart is the Spirit’s work of mortification in the life of the believer. We live in the time of fulfillment, the age in which the Holy Spirit has been received and sent forth to the end that we might “have our mortification.” There is an eschatological dimension to the Spirit’s work. As the fulfillment of the new covenant promise, he communicates all the benefits of Christ’s death to the believer, and effectually works mortification so as to make the “new principle” of life a reality. The Spirit who has been procured for the believer to the end that sin may be mortified.
We are crucified with him [Christ] meritoriously, in that he procured the Spirit for us to mortify sin; efficiently, in that he from his death virtue comes forth for our crucifying; in the way a representation and exemplar we shall assuredly be crucified to unto sin, as he was for our sin…Christ by his death destroying the works of he devil, procuring the Spirit for us, hath so killed sin, as to its reign in believers, that it shall not obtain its end and dominion. A Christian will “assuredly be crucified to sin” because the eschatological Spirit has been sent to implant the believer into Christ.
The Spirit mortifies sin in three different ways. First, the Spirit works in the heart of a believer so as to cause him to abound in the fruits that are contrary to the old man. The fruits of the flesh have been crucified in their passions and lusts so that the new man may walk after the things of the Spirit. Owen describes this as the “renewing of us by the Holy Ghost” Second, the Spirit mortifies sin by “a real physical efficiency on the root and habit of sin for the weakening, destroying, and taking it away.” True mortification occurs when the root of sin is destroyed. The removing of the stony heart is an attack on the root of sin; the Spirit actually consumes and destroys indwelling lusts. Third, the Spirit bridges the gap between Christ and the believer. There is sacramental union so that the believer communes with Christ in his death and fellowships in his sufferings. The cross of Christ is brought near to the believer by faith. Owen viewed these as the three principle workings of the Holy Spirit to effectually work mortification in the life of the believer.
Although the Spirit is the principle cause of mortification, a believer is responsible for his performance of this duty. Owen believed that mortification was the work of the Spirit principally, but functionally, it is the duty of each individual believer. Owen wrote, “He [the Spirit] doth not so work our mortification in us as not to keep it still an act of our obedience. The Holy Ghost works in us and upon us, as we are fit to be wrought in and upon; that is so as to preserve our own liberty and free obedience.” But the Spirit never works against the believer. The workings are always in accord with the corresponding nature of the person. The believer retains all of his individual characteristics and properties so that every act is an act of his own obedience. The Spirit effects, carries on, and accomplishes mortification by his power, but the whole work is retained as the duty of the believer as he acts upon what the Spirit has worked in his heart.
The Spirit, therefore,working upon the heart of the believer will effect and carry on the mortification of sin. A believer must act his faith upon the “death, blood, and cross” of Christ in full expectation that sin will be mortified in the body. It is here that Owen expresses the close connection between mortification and eternal life. A believer should expect deliverance because the nature of Christ’s work was designed to provide such deliverance. The mortification of sin is a supply of grace that belongs to one who is in union with Christ. In Christ, there are innumerable things to engage us towards the expectation of mortification. The Spirit convinces the heart of it's corruption and the need for sin to be mortified, he brings the fullness of Christ and the cross into the heart with its sin-killing power, he establishes the heart to expect relief, and he completes the work of sanctification so that the believer may walk in holiness.
 Ferguson writes, “The law is written in his heart in regeneration, and for Owen this means he receives a new principle of obedience.” Ferguson, Owen, 53.