In this paper we address the two-body problem in massless scalar-tensor (ST) theories within an effective-one-body (EOB) framework. We focus on the first building block of the EOB approach, that is, mapping the conservative part of the two-body dynamics onto the geodesic motion of a test particle in an effective external metric. To this end, we first deduce the second post-Keplerian (2PK) Hamiltonian of the two-body problem from the known 2PK Lagrangian. We then build, by means of a canonical transformation, a ST deformation of the general relativistic EOB Hamiltonian that allows us to incorporate the scalar-tensor (2PK) corrections to the currently best available general relativity EOB results. This EOB-ST Hamiltonian defines a resummation of the dynamics that may provide information on the strong-field regime, in particular, the ISCO location and associated orbital frequency, and can be compared to, other, e.g., tidal, corrections.