Oral administration of Levothyroxine sodium tablets such as Synthroid requires strict dosing conditions to achieve consistent absorption—patients must take the tablet with a full glass of water on an empty stomach, at least 30 to 60 minutes before breakfast, and at least 4 hours apart from drugs that interfere with Levothyroxine Sodium uptake. Furthermore, dose adjustments may be needed when dosing within one hour of certain foods known to affect Levothyroxine Sodium absorption. These stringent requirements often lead to poor adherence and variable bioavailability. To overcome these limitations, a novel sublingual (SL) Levothyroxine Sodium tablet was developed using a direct compression approach optimized for rapid disintegration and mucosal absorption. The formulation was evaluated for physicochemical properties, in vitro dissolution in simulated salivary fluid, in vivo pharmacokinetics in rabbits, and stability under ICH conditions. Dissolution studies in salivary medium (pH 6.5) up to 12 minutes demonstrated 40%, 35%, and 30% Levothyroxine Sodium release for Batches #30, #29C, and #017, respectively. Pharmacokinetic evaluation in Rabbits revealed that Batches #29C and #30 were bioequivalent to Synthroid® (AbbVie Inc.), showing faster absorption (Tmax 4.0–7.0 h) and comparable systemic exposure (AUC₀–₂₄ 99.9–113.3%). Stability testing at 40°C/75% RH (6 months) and 25°C/60% RH, 30°C/65% RH (12 months) confirmed assay retention (95–99%) and related substances within ICH limits. The developed sublingual Levothyroxine sodium, tablet thus represents a clinically advantageous and patient-friendly alternative to conventional oral therapy, eliminating fasting and timing restrictions while maintaining bioequivalent systemic exposure and long-term stability.