This paper evaluates the ability of two different data-driven models to detect and localize simulated structural damage in an in-service bridge for long-term structural health monitoring (SHM). Strain gauge data collected over 4 years is used to characterize the undamaged state of the bridge. The Powder Mill Bridge in Barre, Massachusetts, U.S., which has been instrumented with strain gauges since its opening in 2009, is used as a case study, and the strain gauges used in this study are located at 26 different stations throughout the bridge superstructure. A linear regression (LR) model and an artificial neural network (ANN) model are evaluated based on the following criteria: (a) the ability to accurately predict the strain at each location in the undamaged state of the bridge; (b) the ability to detect simulated structural damage to the bridge superstructure; and (c) the ability to localize simulated structural damage. Both the LR and the ANN models were able to predict the strain at the 26 stations with an average error of less than 5%, indicating that both methodologies were effective in characterizing the undamaged state of the bridge. A calibrated finite element model was then used to simulate damage to the Powder Mill Bridge for three damage scenarios: fascia girder corrosion, girder fracture, and deck delamination. The LR model proved to be just as effective as the ANN model at detecting and localizing damage. A recommended protocol is thus presented for integrating data-driven models into bridge asset management systems.