A large number of aging road and railway riveted metallic bridges suffer from fatigue problems. Stringer-to-floor-beam double-angle bridge connections are among the most fatigue-prone details due to the many cyclic distortion-induced stresses from axle loads. Increasing service loads and corrosion put these components at a higher risk of fatigue cracking. As the replacement of existing structures is costly, lengthy, and thus in some cases almost impossible, the development of retrofitting techniques is of great importance. However, fatigue strengthening of angle connections in bridges is a challenging task. The geometric complexities of these details hinder the development of applicable retrofitting techniques, and the multiaxial stress state in connections complicates fatigue analysis. The first objective of this work is to develop an applicable retrofitting system for strengthening the stringer-to-floor-beam double-angle connections in bridges, considering the fact that the traditional retrofitting techniques such as stop holes, welding additional elements or the softening of connections are not capable of effectively tackling the problem. In recent decades, the application of carbon fiber-reinforced polymer (CFRP) composites has attracted much interest for the fatigue strengthening of metallic structures owing to their superior properties such as high strength, light weight, high corrosion and fatigue resistance. The strengthening system developed in this study consists of a new adhesive-free mechanical wedge–barrel anchor for prestressed CFRP rods and a friction-based clamping system. Extensive finite element simulations are performed to optimize the design of the strengthening system. In addition, the static and fatigue performance of the developed system is experimentally investigated in laboratory tests. The ultimate tensile strength of the strengthening system is found to be greater than the nominal strength of the CFRP rods, which ensures achieving the full capacity of the CFRP rod strength. In addition, the fatigue tests show neither failure of the CFRP rods nor prestressing loss due to slippage in the anchorage components. The second objective is to determine the high-cycle fatigue thresholds for the prediction of crack initiation in angle connections subjected to multiaxial stresses. The critical plane approach is employed as an advanced approach for multiaxial high-cycle fatigue analysis. In addition, the effect of prestressed strengthening is incorporated into multiaxial fatigue models. Using identified proper critical plane-based multiaxial fatigue thresholds, a design approach is proposed for the fatigue strengthening of angle connections subjected to distortion-induced multiaxial stresses. Finally, the third objective is to apply the developed retrofitting system to strengthen the connections of a 92-year-old riveted railway bridge in Switzerland as a demonstration of a field application. The results of the short-term measurements demonstrate the effectiveness of the retrofitting system in improving the high-cycle fatigue behavior of the bridge connections through the reduction of the mean values of the stress components. The post-installation long-term measurements show no prestressing loss in the CFRP rods, indicating that no slippage occurs in the strengthening system components.