Fentanyl use disorder (FUD) drives a persistent public health crisis characterized by high overdose mortality, polysubstance use, and relapse rates >50% despite medications for opioid use disorder (MOUD). Although U.S. drug overdose deaths declined from >110,000 in 2022–2023 to ~80,000–85,000 in 2024, synthetic opioids including fentanyl remain responsible for ~70% of cases and impose an annual economic burden exceeding $1.5 trillion. Current pharmacological treatments reduce overdose risk but are limited by incomplete reward blockade, persistent craving and anhedonia, treatment dropout, side effects, and new dependencies. Existing non-invasive neuromodulation approaches lack the spatial resolution and depth to target addiction circuitry precisely. This dissertation investigates low-intensity focused ultrasound (LIFU)—a non-invasive, reversible technique with millimeter-scale precision and deep brain penetration—as a novel therapeutic in a rat model of FUD. Using intermittent-access fentanyl self-administration to model human escalation and relapse, this work integrates behavioral testing, in vivo fast-scan cyclic voltammetry, bulk RNA-sequencing with cell-type deconvolution, western blotting, flow cytometry, and immunohistochemistry. Findings demonstrate temporally biphasic withdrawal: early hyperexcitability (days 1–3) with glutamatergic hyperactivity and reduced GABAergic tone, followed by late hypoactivity (days 12–15) featuring >70% dopamine depletion, anhedonia, and mesocorticolimbic synaptic collapse. Marked sex differences emerge—females show initial ~40% dopamine surges but severe late-phase AKT-mTOR shutdown, whereas males exhibit sustained GSK3β activation and excessive synaptic pruning. Prelimbic cortex-targeted LIFU enables bidirectional, frequency-dependent dopamine modulation in the nucleus accumbens: inhibitory parameters suppress release by 58%, excitatory parameters (sex-optimized) enhance it by 28–30%. Transcriptomic profiling identified 2,391 differentially expressed genes during withdrawal. Although buprenorphine reduces reinstatement and normalizes 115 fentanyl-dysregulated genes, it induces 1,044 novel remodeling genes. In contrast, phase- and sex-matched LIFU attenuates cue- and drug-primed reinstatement by 50–57%, restores excitatory/inhibitory balance and gene expression profiles, and suppresses relapse without compensatory transcriptional changes. This work establishes LIFU as a precise, non-pharmacological tool for circuit-specific restoration in FUD, providing the first preclinical evidence of phase- and sex-tailored ultrasound neuromodulation and a direct translational pathway for clinical application in opioid addiction.