Background <p>Early breastfeeding initiation is crucial for low-birth-weight (LBW) infants, yet in-person lactation support may be limited in resource-poor settings. Telemedicine holds promise but lacks robust comparative evidence with traditional care.</p> Objective <p>To evaluate whether nurse-led telemedicine is non-inferior to in-person support on routine early-initiation performance in LBW/NICU settings, and to describe breastfeeding processes within 24 h postpartum.</p> Methods <p>This parallel-group, non-inferiority randomized controlled trial included 200 mothers of LBW infants admitted to four neonatal intensive care units (NICUs) in Egypt. Participants were randomized (1:1) to receive nurse-led telemedicine or standard in-person lactation support. Primary Process Outcome: Direct Breastfeeding Initiation within 1 Hour, assessed against a 5% non-inferiority margin. Secondary outcomes of maternal self-efficacy, satisfaction, state anxiety, and infant growth parameters were measured at baseline, one week, and one month postpartum. Analyses followed both intention-to-treat and per-protocol approaches.</p> Results <p>Breastfeeding initiation occurred in 65% of mothers in the telemedicine group versus 70% in the in-person group, confirming non-inferiority (<i>p</i> = 0.04). Although in-person support provided a minor short-term advantage in maternal self-efficacy at one week (49.2 ± 6.5 vs. 47.5 ± 7.2, <i>p</i> = 0.03), scores converged by one month (<i>p</i> = 0.45). Telemedicine participants reported higher satisfaction with accessibility (<i>p</i> = 0.03), while overall support quality, anxiety reduction, and infant growth measures were comparable between groups. Parity and socioeconomic status independently predicted breastfeeding initiation (<i>p</i> &lt; 0.01).</p> Conclusions <p>Nurse-led telemedicine did not reduce first-hour initiation relative to in-person support; given stabilization protocols in LBW/NICU care, this endpoint functions as a process benchmark rather than a direct target of the support modality. Although in-person support may offer early advantages in maternal self-efficacy, telemedicine effectively sustains key outcomes over time and can expand equitable breastfeeding support in regions with limited healthcare resources.</p> Trial registration <p>ClinicalTrials.gov NCT06652386, Registered 22 October 2024.</p>