A simple chemometric-assisted UV-spectrophotometric method was used to study the compatibility of clindamycin hydrochloride (HC1) with two commonly used natural controlled-release polymers, alginate (Ag) and chitosan (Ch). Standard mixtures containing 1:1, 1:2, and 1:0.5 w/w drug–polymer ratios were prepared and UV scanned. A calibration model was developed with partial least square (PLS) regression analysis for each polymer separately. Then, test mixtures containing 1:1 w/w drug–polymer ratios with different sets of drug concentrations were prepared. These were UV scanned initially and after three and seven days of storage at 25 °C. Using the calibration model, the drug recovery percent was estimated and a decrease in concentration of 10% or more from initial concentration was considered to indicate instability. PLS models with PC3 (for Ag) and PC2 (for Ch) showed a good correlation between actual and found values with root mean square error of cross validation (RMSECV) of 0.00284 and 0.01228, and calibration coefficient (R2) values of 0.996 and 0.942, respectively. The average drug recovery percent after three and seven days was 98.1 ± 2.9 and 95.4 ± 4.0 (for Ag), and 97.3 ± 2.1 and 91.4 ± 3.8 (for Ch), which suggests more drug compatibility with an Ag than a Ch polymer. Conventional techniques including DSC, XRD, FTIR, and in vitro minimum inhibitory concentration (MIC) for (1:1) drug–polymer mixtures were also performed to confirm clindamycin compatibility with Ag and Ch polymers.