This study aims to assess the prevalence of potentially inappropriate medications (PIMs) and to analyze the relationship between the PIMs and frailty among inpatient older adults aged 65 and above in Saudi Arabia. A retrospective cross-sectional study design was utilized during the period between April 2021 and April 2022 of all patients aged 65 years and above admitted in a public tertiary hospital in Saudi Arabia. Data on the number of medications and the use of PIMs were assessed using Beers’ criteria while the frailty status was assessed using the “FRAIL Scale”. Of the 358 patient files that were reviewed, 52.2% were males, 60.9% were aged 65–74 years, and 82% were married. The prevalence of robust, prefrail, and frail patients was 5%, 36.9%, and 58.1%, respectively. According to the 2019 Beers criteria, a total of 45.8% (n = 164) participants identified as using PIMs. Compared to the non-PIMs group, the PIMs group demonstrated significant differences in the number of medications (p < 0.001), the number of comorbidities (p < 0.05), and the frailty score (p < 0.001). The strongest predictor of PIM use was a number of comorbidities, recording an odds ratio of 2.86, (95% CI 1.21–6.77, p < 0.05). Our results show that the use of PIM was significantly associated with frail older adults with multiple comorbidities and in patients with polypharmacy. A clear assessment and evaluation tool may improve the quality of drug treatment in the older adult population, particularly in frail patients.