Antibiotic resistance has been among the top public health threats elsewhere. Scientific information on knowledge, attitudes, and practices (KAP) at the community level towards antibiotic use and disposal ways is a vital step for effective intervention. This study aimed at determining the levels of KAP and associated risk factors for antibiotics in and around Hawassa City, southern Ethiopia. A community-based cross-sectional study was conducted, and data were collected using a structured questionnaire. Descriptive statistics, chi-square test, and logistic regression were used to analyze and interpret the results. A total of 504 participants with a mean age of 35.32 ± 9.03 years were included in the study. Most of the participants were urban dwellers (59.5%); more than half (55.6%) of the participants were male; most of the participants (62.7%) were at least college graduates; about half were employed (52.4%); about 41.7% of the participants had a large family size (≥7) with a mean family size of 5.7 ± 2.7; the average family monthly income was ETB 7213.71 ± 3673, and over three-fourth (74.8%) of the study participants were married. In addition, about 83.13% of the study participants heard about antibiotics; almost all of them (99.8%) had ever used antibiotics at some point in their life (75% of which used antibiotics within 6 months), and all of them could name at least one common type of antibiotic. Moreover, most of the participants (86.5%) did not receive any training related to antibiotics, and 29.4% of them obtained antibiotics without a prescription. Most participants had poor knowledge (64%), negative attitudes (60.4%), and poor practices (55%) towards antibiotic use, resistance, and disposal methods. Significant and positive linear correlations between knowledge and attitude (r = 0.539, P ≤ 0.001), knowledge-practice (r = 0.532, P ≤ 0.001), and attitude-practice (r = 0.786, P < 0.001) were also observed. Most of the sociodemographic variables were significantly associated with the mean KAP scores of the study participants. Living in a rural area, having a large family size, and being female, married, illiterate, and farmer resulted in a very low level of knowledge. Similarly, living in a rural area, having a small family size, and being older and married resulted in a negative attitude. Furthermore, having a smaller family size, having a low family monthly income, and being married, illiterate, and self-employed resulted in poor practice. A very low level of KAP towards antibiotics among people living in and around Hawassa City calls for urgent and effective intervention strategies.