This expression is used in Ephesians 6:18 and Jude 20. 

Jude 17-21: “Beloved, remember ye the words which were spoken before of the apostles of our Lord Jesus Christ, how that they told you there should be mockers in the last time, who should walk after their own desires. These be they who separate themselves [from the truth and its spirit], sensual [minding earthly things, and gratifying the ambitions and tastes of the old nature], having not the spirit. But ye, beloved, building up yourselves on your most holy faith, praying with a holy spirit [a spirit of loyalty and devotion to God], keep yourselves in the love of God, looking for the mercy of our Lord Jesus Christ unto eternal life.” 

“Praying in (or “with” in some translations) the holy spirit” means praying with a spirit of loyalty and devotion to God, with heart appreciation for what we are doing.

The purpose of prayer is to bring our hearts into alignment with God’s will, preparing us to receive His blessings in a meaningful way. God desires that we approach Him sincerely, not with empty repetitions, and that our prayers reflect submission to His wisdom rather than merely seeking temporal needs.

Unlike the world, which prays for physical necessities or personal victories, God’s children should prioritize spiritual sustenance—asking for the “bread from heaven,” growing in the fruit of the holy spirit, and seeking holiness above all. The body itself is merely an instrument for spiritual development, meant to be used in service to God until His purpose for it is fulfilled.

As “new creatures,” believers must pray with a focus on their spiritual needs, trusting that God, who is eager to give good things, will provide all necessary provisions according to His perfect plan. Prayer should be an act of faith, a surrender of self-will, and a continual desire for transformation into God’s likeness.

Additional Resources:
Booklet (PDF): “How God Answers Prayer”
Booklet (PDF): “The Holy Spirit”

Christian Questions Podcast 
Episode 1294: “How Can I Transform My Prayer Life? (Part I)”
Who God hears, why He says no and how prayer works
Preview Video
CQ Rewind Show Notes

Episode #1325: “Does God’s Holy Spirit Speak to Us?”
Unfolding how the holy spirit does and does not function in our lives
Preview Video
CQ Rewind Show Notes