The combined effects of subsurface drip irrigation (SDI), nitrogen (N) application, and plant growth regulator (PGR) application rates on the upland cotton (Gossypium hirsutum) performance in the Upper Southeast Coastal Plain remain poorly understood. This study aimed to enhance cotton productivity and economic returns by evaluating SDI strategies and their interactions with the PGR application rates, N management, and variety selection. Over three growing seasons (2019–2021), two experiments were conducted at the Tidewater Agricultural Research Center (TAREC) in Suffolk, Virginia. Experiment 1 explored the effect of three dripline spacings (0.91 m, 1.82 m, no irrigation), four PGR application rates (0%, 100%, 150%, 200%), and four cotton varieties, revealing significant impacts of the dripline spacing and PGR application rate on the lint yield and economic gains. The 1.82 m dripline spacing and 100% PGR application rate consistently produced superior lint yields and profits. Experiment 2 evaluated the effects of three irrigation strategies (0.91 m dripline spacing, 0.91 m dripline spacing + fertigation, no irrigation), three N application rates (89, 133, and 178 kg ha⁻¹), three PGR application rates, and two varieties, highlighting an optimal N application rate of 133 kg ha⁻¹ for increasing the lint yield in 2 of 3 years and the adverse effects of higher PGR application rates. The findings demonstrated the importance of employing tailored SDI systems integrating variety selection and adaptive management strategies. These results underscore the potential to improve cotton's productivity, profitability, and sustainability in diverse environments in the Southeast Coastal Plain and similar cotton-growing regions in the U.S.