Background: Hypertension is a global public health challenge that contributes to the burden of hypertensive heart disease, stroke, renal failure, premature morbidity, and mortality. The availability of effective antihypertensive medications didn’t bring expected outcomes in terms of adherence for antihypertensive medication. Objective: The aim of this study was to assess antihypertensive medication adherence and associated factors among adult hypertensive patients at Dilla university referral hospital, Southern Ethiopia, 2021. Methods: A hospital-based cross-sectional study was conducted, at Dilla University Referral Hospital from June 10, 2021, to July 10, 2021, and 205 study participants were selected from the study population using a systematic random sampling procedure. Patients in the study were interviewed while their medical records were reviewed using a data abstraction sheet. Adherence was assessed using an eight-item Morisky Medication adherence scale (MMAS-8); a MMAS-8 score of less than 6 was considered non-adherence, and a MMAS-8 score greater than or equal to 6 was considered adherence. Factors associated with adherence were identified using binary and multivariate logistic regression analyses. The crude odds ratio and adjusted odds ratio with a 95% confidence interval were calculated using SPSS version 20. Variables with a P-value <0.05 in the multivariable analysis were assumed to be statistically significant factors. Results: 205 respondents were interviewed, with a response rate of 100%. More than half (57.6%) of the study participants were male. 65.3% (58.784–71.816) of the study participants were found to be adherent to their medication. Longer Duration of diagnosis of hypertension (AOR =0.280, 95% CI = 0.025–0.836), participants who can’t read and write (AOR = 0.40, 95% CI = 0.00-0840), and traditional drug users (AOR =0.15, 95% CI =0.003-0.489) were inversely significant associated with antihypertensive medication adherence. Conclusion: An adhesion level of 65.3% was found to be suboptimal. Traditional drug users, being uneducated and the duration of the diagnosis of hypertension were adversely influencing medication adherence. Therefore, routine health education and awareness creation are strongly recommended