This review critically examines the mechanisms by which winemaking processes and preservation techniques modulate the retention of bioactive compounds, shaping wine’s nutraceutical potential. Traditional practices (fermentation dynamics, barrel aging) and modern innovations (non-Saccharomyces yeasts, CRISPR engineering, enzyme-assisted extraction) are scrutinized for their impact on bioactive composition, emphasizing heat, oxygen and sulphite sensitivity. Preservation strategies from SO₂ to pulsed electric fields and nanotechnology are evaluated for balancing microbial stability, oxidation control and consumer demands. Wine’s polyphenols (resveratrol, quercetin), flavonoids and anthocyanins demonstrate cardioprotective, antioxidant and microbiota-modulating effects, yet controversies persist, alcohol’s health risks counterpose bioactive benefits, while epidemiological ambiguities in dosage-response relationships and confounding lifestyle factors challenge causal inferences. Case studies contrasting organic/conventional production and aging methods reveal trade-offs between sensory quality and bioactive retention. This review hypothesizes that synergistic integration of precision technologies (e.g., CRISPR yeast engineering, AI-driven fermentation) with non-thermal preservation can maximize bioactive retention while mitigating health risks. Urgency stems from consumer demand for health-functional wines and regulatory pressures to reduce sulphites and alcohol. Critical gaps remain in elucidating bioavailability mechanisms; sustainable processing aligned with circular economy principles and harmonizing health claims with regulatory frameworks. The review advocates for precision enology and transdisciplinary collaboration to advance wine as a functional food, urging rigorous, evidence-based innovation to reconcile tradition with health science, ensuring safety and efficacy in redefining wine’s cultural and nutraceutical legacy.