The　electrochemical　acetonitrile　(CH3CN)　reduction　reaction　provides　an　alternative　to　produce　ethylamine　(CH3CH2NH2)　under　ambient　conditions　but　remains　challenging.　Using　density　functional　theory　(DFT)　calculations,　we　explored　the　catalytic　performance　of　four　types　of　graphene-based　single-atom　catalysts　(SACs)　total　of　32　materials　toward　the　CH3CN　reduction　reaction.　We　identified　that　two　highly　stable　SACs,　namely　Cr@N4　and　Mn@N4,　can　greatly　accelerate　both　reaction　thermodynamics　and　kinetics　with　small　energy　barriers.　In　particular,　these　two　SACs　can　effectively　suppress　the　competitive　hydrogen　evolution　reaction　(HER)　by　selective　adsorption　of　key　intermediate　of　*CH3CN　rather　than　*H,　which　feature　superior　catalytic　selectivity.　More　impressively,　the　activity　trends　of　various　candidates　can　be　directly　correlated　to　the　adsorption　energy　of　*CH3CHN　(ΔE(*CH3CHN)),　and　the　underlying　activity　origin　is　ascribed　by　the　enhancement　of　the　adsorption　for　the　*CH3CHN.　Furthermore,　detailed　electronic　property　analyses　indicate　that　the　bonding/anti-bonding　interactions　of　different　active　metal　centers　with　*CH3CHN　are　the　key　factor　determining　the　adsorption　strength.　The　more　bonding　contributions　below　the　Fermi　level　(Ef)　lead　to　the　stronger　*CH3CHN　combination　on　active　metal　centers,　while　the　anti-bonding　state　is　opposite.　As　a　result,　Cr@N4　stands　out　among　these　candidates,　which　can　tune　the　performance　of　acetonitrile　reduction　reaction　by　balancing　the　reactivity　of　CH3CN　and　the　desorption　of　CH3CH2NH2.　Our　results　unveil　that　the　excellent　catalytic　activity　of　Cr@N4　for　CH3CN　reduction　reaction　can　be　further　confirmed　by　calculating　the　bond　lengths　and　charge　variations.　With　the　elongation　of　C[tbnd]N　bond　in　the　adsorbed　CH3CHxNHy,　CH3CN　molecule　can　be　effectively　activated　on　Cr@N4.　Overall,　this　work　addresses　a　promising　active　catalyst　and　will　be　of　a　guidance　of　great　theoretical　significance　to　construct　carbon-based　materials　supported　transition　metal　single-atom　electrocatalysts　for　the　CH3CN　reduction　reaction.　©　2022