Here, one step, simple preparation of superporous p(β-cyclodextrin) (p(β-CD)) cryogels in the presence of various ratios of crosslinker, divinyl sulfone (DVS) e.g., 100, 150, 200% mole with respect to the mole ratio of 6 hydroxyl groups on β-CD unit under cryogenic conditions were reported for the first time. The swelling properties, and hydrolytic degradation of p(β-CD) cryogels was directly related to the used crosslinker ratio. It was observed that the p(β-CD) cryogels showed higher swelling% in DMSO and DMF than in DI water. The prepared p(β-CD)-1 cryogel that was 100% crosslinked exhibited 14 ± 3.7%, 34 ± 4.8%, and 45 ± 6.2% weight losses within 20 days in pH 5.4, 7.4, and 9.0 buffer solutions, respectively. An acceptable hemolysis index of < 5% and a blood coagulation index, >89% were observed for the p(β-CD) cryogels at 1 mg/mL concentrations. Additionally, the potential useability of p(β-CD) cryogels as in vitro drug delivery systems for both hydrophilic vancomycin, and hydrophobic tetracycline as model drugs were individually illustrated at pH 7.4 in PBS. The cumulative drug release from p(β-CD) cryogels, in sustained release profiles with 76.7 ± 9.0 mg/g of vancomycin (89.9 ± 10.5% of the loaded amount) and 146.5 ± 19.4 mg/g tetracycline g (83.1 ± 6.3% of the loaded amount) were attained in 6 and 54 h, respectively at pH 7.4 in PBS. Most importantly, p(β-CD) cryogels exhibited simultaneous loading and releasing the ability for both hydrophilic vancomycin, and hydrophobic tetracycline drugs by concurrently releasing 37.0 ± 2.7 mg/g (23.4 ± 1.8% of the loaded amount), and 36.3 ± 1.3 mg/g (23.6 ± 0.8% of the loaded amount), respectively at pH 7.4 (PBS) in 10 h.