BACKGROUND Methadone and buprenorphine-naloxone (Suboxone®) have been discussed and compared extensively in the medical literature as effective treatments for opioid use disorder (OUD). While the evidence basis for the use of these medications is very favorable, less is known about the perceptions of these medications within the general public. OBJECTIVE This study aimed to use social media, specifically Twitter, to assess the public perception of these medications, and to compare the discussion content between each medication based on theme, subtheme, and sentiment. METHODS We conducted a mixed methods descriptive study analyzing individual microposts (“tweets”) that mentioned “methadone” or “suboxone”. We then categorized these tweets into themes and subthemes, as well as by sentiment and personal experience, and compared the information posted about these two medications, including in tweets that mentioned both medications. RESULTS We analyzed 900 tweets, most of which related to access (13.8% for methadone; 12.9% for suboxone®), stigma (15.3%; 14.0%), and OUD treatment (11.5%; 5.4%). Only a small proportion of tweets (16.4% for suboxone® and 9.3% for methadone) expressed positive sentiments about the medications, with few tweets describing personal experiences. Tweets mentioning both medications primarily discussed MOUD in general, rather than comparing the two medications directly. CONCLUSIONS Twitter content about methadone and suboxone are similar, with the same major themes and similar sub-themes. Despite the proven effectiveness of these medications, there was little dialogue related to their benefits or efficacy in the treatment of opioid use disorder. Perceptions of these medications may contribute to their underutilization in combatting opioid use disorder.