Pseudomonas aeruginosa is a bacterium with high antimicrobial resistance to several drugs including carbapenems. Recently, resistance to cefiderocol (FDC), a new siderophore cephalosporin, has been reported despite its rare use in clinical practice. Therefore, this study aimed to investigate the dynamics of different resistance mechanisms in P. aeruginosa that evolve under FDC pressure, as well as the interactions between these mechanisms in evolutionary trajectories to guide clinical medication. P. aeruginosa ATCC 27853 was continuously induced with subinhibitory concentrations of cefiderocol in vitro to generate strains with different resistance levels. Phenotypic adaptability and molecular regulatory networks during the evolution of resistance were systematically elucidated using growth curves, pairwise competition assays, transcriptomics, RT-qPCR and efflux inhibition assays. The minimum inhibitory concentration (MIC) of the induced FDC-resistant strain increased from 0.125 to 64 μg/mL. Simultaneously, the growth rate and peak declined below those of the parental strain. The pairwise competition assay showed that the relative fitness of resistant strains versus parental strains was < 1 in LB and ID-CAMHB broths. Transcriptome analysis revealed that the MIC of the induced FDC-resistant strain was related to the dose of efflux pumps, together with a layer-by-layer regulation of gene expression, to adapt to environmental stress. In the initial resistant strain, efflux pumps were slightly upregulated, and energy metabolism was downregulated. Conversely, in the strain with a MIC of 64 μg/mL, efflux pumps were significantly up-regulated and drove bacterial reprogramming to induce resistance, particularly the RND efflux pump component oprM, along with multiple ABC transporters. RT-qPCR validated the significant upregulation of oprM, opuC, and opuBD ( p < 0.05), confirming their central role. Furthermore, in the presence of the efflux pump inhibitor phenyl-arginine β-naphthylamide (PAβN), the resistant strains exhibited significantly reduced MICs for FDC. In conclusion, these data indicate that multiple mechanisms of action are involved in the antibacterial activity of P. aeruginosa against FDC. Notably, the evolution of resistance was associated with the dose-dependent upregulation of core efflux pumps, complemented by stage-specific global physiological remodeling; however, it also came at a fitness cost.