Current research studies on progressive collapse of reinforced concrete (RC) moment frames mainly focus on the RC frames with strong horizontal restraints in which collapse only propagates in the vertical direction. Notwithstanding, progressive collapse may propagate in the horizontal direction due to insufficient lateral stiffness and bearing capacity of the real-world structural systems, eventually triggering a wider range of damage associated with a disproportionate collapse. A static collapse test on three asymmetric beam-column substructure specimens with flange slabs was conducted to analyse the effects of different lateral restraints on the progressive collapse behaviour of RC beam-column specimens. The three specimens, including two one-story and one two-story substructures, are designated as OP, TP and OA, in which OP and OA represent one-story penultimate and antepenult column removal scenarios, respectively, while TP represents a two-story penultimate column removal scenario. Comparing to OP, an extra bay and an extra floor were added in OA and TP, respectively, to create different horizontal restraint scenarios. Experimental results show that under the compressive arch action (CAA), the contribution of the CAA within the beams and slabs in OP and TP was significantly reduced compared to that in OA. Under the catenary action (CA), the collapse resistance of OA was found to develop rapidly to exceed even the peak resistance of CAA, whereas the resistance of OP and TP varied marginally, caused by the continuously released axial force of rebars within the beams and flange slabs. Additionally, the final failure mode of all three specimens demonstrated a compression-bending failure of the edge and penultimate columns. Subsequent to the experiments, a fibre-beam-element-based model was built to analyse the development of the internal forces within the slab-flange beams and columns. In the numerical analyses, the penultimate column in OA was found to damage prior to the edge column, owing to its larger axial force generated from the redistributed force and the additional bending moment. While in TP, the so-called Vierendeel truss action led to an uneven internal force distribution developed within the two floors, causing the failure to propagate from the lower story to the upper story. Finally, design recommendations are provided based on the results obtained from the experimental test and numerical simulation.