Biocomposite hydrogels based on nanocellulose fibers (CNFs), low methoxy pectin (LMP), and sodium alginate (SA) were fabricated via the chemical crosslinking technique. The selected CNFs-based hydrogels were loaded with clindamycin hydrochloride (CM), an effective antibiotic as a model drug. The properties of the selected CNFs-based hydrogels loaded CM were characterized. The results showed that CNFs-based hydrogels composed of CNFs/LMP/SA at 1:1:1 and 2:0.5:0.5 mass ratios exhibited high drug content, suitable gel content, and high maximum swelling degree. In vitro assessment of cell viability revealed that the CM-incorporated composite CNFs-based hydrogels using calcium ion and citric acid as crosslinking agents exhibited high cytocompatibility with human keratinocytes cells. In vitro drug release experiment showed the prolonged release of CM and the hydrogel which has a greater CNFs portion (C2P0.5A0.5/Ca + Ci/CM) demonstrated lower drug release than the hydrogel having a lesser CNFs portion (C1P1A1/Ca + Ci/CM). The proportion of hydrophilic materials which were low methoxy pectin and sodium alginate in the matrix system influences drug release. In conclusion, biocomposite CNFs-based hydrogels composed of CNFs/LMP/SA at 1:1:1 and 2:0.5:0.5 mass ratios, loading CM with calcium ion and citric acid as crosslinking agents were successfully developed for the first time, suggesting their potential for pharmaceutical applications, such as a drug delivery system for healing infected wounds.