In this study, ciprofloxacin (CIP)-loaded microspheres were formulated using alginate and cress seed mucilage as natural polymeric carriers; microspheres were prepared via ionic gelation, facilitating the effective encapsulation of CIP. The swelling kinetics of the microspheres were evaluated under different physiological pH conditions (1.2, 6.8, and 7.4) to simulate the acidic and intestinal environments. The results showed minimal swelling at pH 1.2, while significantly higher swelling was observed at pH 6.8 and 7.4, indicating pH-responsive behavior. Characterization and in vitro release studies confirmed the successful incorporation of CIP into the microspheres without compromising their functional properties. The Korsmeyer–Peppas model was the best fit for drug release data, indicating that ciprofloxacin release followed a non-Fickian (anomalous) diffusion pattern, representing a synergistic contribution of both diffusion and polymer chain relaxation mechanisms. The microspheres exhibited promising potential for drug delivery, while antibacterial assays demonstrated a significant inhibitory effect, attributed to the sustained release of ciprofloxacin. This study highlights the potential of alginate and cress seed-based microspheres as efficient carriers for the controlled release of ciprofloxacin.