Aiming to address the challenges of uneven precipitation distribution and seasonal drought constraints in high-altitude tobacco-growing areas, this study was conducted to scientifically develop irrigation strategies for flue-cured tobacco. Taking ‘Honghua Dajinyuan’ as the experimental cultivar, field trials were carried out in Huidong County and Huili City of Liangshan Prefecture, Sichuan Province. Four treatments were established, including optimized irrigation during the root extension stage (S1), optimized irrigation during the vigorous growth stage (S2), full-stage optimized irrigation (S3), and natural precipitation (CK, control). The impacts of these water supply regimes on leaf development, physical properties, economic traits, and chemical composition were systematically analyzed. S3 exhibited the most significant promotion effect on leaf length. Specifically, compared with CK, the leaf length of S3 at the mature stage in Huidong increased significantly by 6.48%. S2 and S3 significantly increased the thickness of palisade tissue, spongy tissue, and total leaf thickness in the middle leaves but had limited effects on leaf width. For physical traits, S2 and S3 significantly enhanced the leaf thickness and leaf area density of cured tobacco leaves. S2 increased leaf thickness by 16.89% in Huidong and 7.87% in Huili, whereas S3 increased leaf area density by 18.77% in Huidong and 8.13% in Huili, accompanied by reduced stem content. In terms of economic performance, S3 improved the yield by 15.09% in Huidong and 3.54% in Huili, and the output value by 16.62% in Huidong and 6.09% in Huili, with the highest proportion of high- and medium-grade tobacco leaves. For chemical composition, S2 showed better coordination, characterized by a high potassium-to-chloride ratio and appropriate sugar-to-alkaloid and nitrogen-to-alkaloid ratios. Considering both of efficacy and cost, an optimized irrigation strategy is recommended for high-altitude tobacco-growing areas: no irrigation during the root extension stage, prioritized irrigation during the vigorous growth stage, and demand-based irrigation during the mature stage. In future research, irrigation parameters can be refined by integrating soil types and annual climate patterns, and the synergistic regulation mechanism of water and fertilizer should be further explored, so as to provide more precise technical support for high-quality and efficient tobacco production in high-altitude areas.