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Background/Objectives: Piperazine constitutes a versatile heterocyclic core commonly used in drug development because of its ability to engage with different biological targets. The current research focuses on the computation-based drug-likeness analysis, gastrointestinal absorption prediction, and toxicity estimation of derivatives (1–27) of piperazine, where four compounds (1–4) belong to the list of commercially available drugs. Methods: Parameters related to drug-likeness, solubility and bioavailability were calculated by using the SwissADME and ADMETlab 3.0 web tools as well as MoloVol software (v1.2.0) and MarvinSketch software (v4.1.13). Aftewards, GI absorption, blood-brain barrier permeability, P-glycoprotein recognition and CYP450 inhibition were modeled. The toxicological characteristics were assessed by DataWarrior software (v06.05.04), which classified compounds as mutagenic, carcinogenic, reproductive, and irritant. Results: According to the BOILED‑Egg approach, compounds 2, 4–6, 10–21, 23–25, and 27 were estimated to exhibit good blood–brain barrier permeation. Majority of compounds (1–4, 7–9, 14, 16, 17, and 19–25) were recognized as P-glycoprotein substrates. The metabolic profile suggested inhibition of different CYP450 enzymes: 1A2, 2C19, 2C9, 2D6, and 3A4. None of the compounds (1–27) were indicated to pose mutagenic hazard. Compounds 5 and 13 were predicted to be carcinogenic. Compounds 6, 12, and 14 were anticipated to exhibit reproductive toxicity. Compounds 11–15 were expected to act as irritants. Conclusions: Computational data generate several hypotheses requiring further experimental validation of studied compounds as promising antiparasitic drugs (7, 8, 10), an antimicrobial drug (11), a neuroactive drug (16), anti-inflammatory drugs (18, 20–24), antitubercular drugs (25, 26), and an antitumor drug (27).